bims-lysosi Biomed News
on Lysosomes and signaling
Issue of 2022–06–26
forty-four papers selected by
Stephanie Fernandes, Max Planck Institute for Biology of Ageing
  1. Parkinson's disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes.
  2. Impaired Mitophagy in Sanfilippo A mice Causes Hypertriglyceridemia and Brown Adipose Tissue Activation.
  3. Massive Accumulation of Sphingomyelin Affects the Lysosomal and Mitochondria Compartments and Promotes Apoptosis in Niemann-Pick Disease Type A.
  4. Borcs6 is required for endo-lysosomal degradation during early development.
  5. Past, present, and future perspectives of transcription factor EB (TFEB): mechanisms of regulation and association with disease.
  6. Lysosome Interference Enabled by Proton-Driven Dynamic Assembly of DNA Nanoframework inside Cells.
  7. Targeted protein degradation via the autophagy-lysosome system: AUTOTAC (AUTOphagy-TArgeting Chimera).
  8. Glycan degradation promotes macroautophagy.
  9. Functional Characterization of CLCN4 Variants Associated With X-Linked Intellectual Disability and Epilepsy.
  10. Age-Related Lysosomal Dysfunctions.
  11. Unexpected Phenotype Reversion and Survival in a Zebrafish Model of Multiple Sulfatase Deficiency.
  12. The Translational Regulation in mTOR Pathway.
  13. Tralesinidase alfa enzyme replacement therapy prevents disease manifestations in a canine model of mucopolysaccharidosis type IIIB.
  14. The central role of mTORC1 in amino acid sensing.
  15. Quantitation of a Urinary Profile of Biomarkers in Gaucher Disease Type 1 Patients Using Tandem Mass Spectrometry.
  16. Balancing nutrient and energy demand and supply via autophagy.
  17. Treatment of Neuronopathic Mucopolysaccharidoses with Blood-Brain Barrier-Crossing Enzymes: Clinical Application of Receptor-Mediated Transcytosis.
  18. Novel roles of mTORC2 in regulation of insulin secretion by actin filament remodeling.
  19. TFEB ameliorates autophagy flux disturbance induced by PBDE-47 via up-regulating autophagy-lysosome fusion.
  20. A YAP/TAZ-TEAD signalling module links endothelial nutrient acquisition to angiogenic growth.
  21. Role of mTOR Signaling Cascade in Epidermal Morphogenesis and Skin Barrier Formation.
  22. LRRK2 and Proteostasis in Parkinson's Disease.
  23. A compound directed against S6K1 hampers fat mass expansion and mitigates diet-induced hepatosteatosis.
  24. Proteasomal inhibition preferentially stimulates lysosome activity relative to autophagic flux in primary astrocytes.
  25. The ESCRT Machinery: Remodeling, Repairing, and Sealing Membranes.
  26. Sorting Through the Extensive and Confusing Roles of Sortilin in Metabolic Disease.
  27. Autophagy: Identification of MTMR5 as a neuron-enriched suppressor.
  28. PF-06409577 inhibits renal cyst progression by concurrently inhibiting the mTOR pathway and CFTR channel activity.
  29. ConducTORs of a Signaling Symphony: Metabolic and Hormone Responses Converge on TOR and EIN2 in plants.
  30. Cholesterol and matrisome pathways dysregulated in astrocytes and microglia.
  31. An mTOR and DNA-PK dual inhibitor CC-115 hinders non-small cell lung cancer cell growth.
  32. Actin remodelling controls proteasome homeostasis upon stress.
  33. Pathogenic LRRK2 regulates centrosome cohesion via Rab10/RILPL1-mediated CDK5RAP2 displacement.
  34. Promising Effect of High Dose Ambroxol Treatment on Neurocognition and Motor Development in a Patient With Neuropathic Gaucher Disease 2.
  35. CRISPR/Cas9-Mediated Constitutive Loss of VCP (Valosin-Containing Protein) Impairs Proteostasis and Leads to Defective Striated Muscle Structure and Function In Vivo.
  36. Rapamycin Dampens Inflammatory Properties of Bone Marrow ILC2s in IL-33-Induced Eosinophilic Airway Inflammation.
  37. Toxic Metabolites and Inborn Errors of Amino Acid Metabolism: What One Informs about the Other.
  38. The Inositol Phosphate System-A Coordinator of Metabolic Adaptability.
  39. eIF5B and eIF1A reorient initiator tRNA to allow ribosomal subunit joining.
  40. SNARE assembly enlightened by cryo-EM structures of a synaptobrevin-Munc18-1-syntaxin-1 complex.
  41. A MademoiseLLE domain binding platform links the key RNA transporter to endosomes.
  42. Supramolecular assembly of GSK3α as a cellular response to amino acid starvation.
  43. Thirty-year clinical outcomes after haematopoietic stem cell transplantation in neuronopathic Gaucher disease.
  44. mTOR Inhibitor Treatment in Patients with Tuberous Sclerosis Complex Is Associated with Specific Changes in microRNA Serum Profile.
  1. Cell. 2022 Jun 23. pii: S0092-8674(22)00652-3. [Epub ahead of print]185(13): 2292-2308.e20
    Parkinson's disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes.
    Meiqin Hu, Ping Li, Ce Wang, Xinghua Feng, Qi Geng, Wei Chen, Matangi Marthi, Wenlong Zhang, Chenlang Gao, Whitney Reid, Joel Swanson, Wanlu Du, Richard I Hume, Haoxing Xu.
      Lysosomes require an acidic lumen between pH 4.5 and 5.0 for effective digestion of macromolecules. This pH optimum is maintained by proton influx produced by the V-ATPase and efflux through an unidentified "H+ leak" pathway. Here we show that TMEM175, a genetic risk factor for Parkinson's disease (PD), mediates the lysosomal H+ leak by acting as a proton-activated, proton-selective channel on the lysosomal membrane (LyPAP). Acidification beyond the normal range potently activated LyPAP to terminate further acidification of lysosomes. An endogenous polyunsaturated fatty acid and synthetic agonists also activated TMEM175 to trigger lysosomal proton release. TMEM175 deficiency caused lysosomal over-acidification, impaired proteolytic activity, and facilitated α-synuclein aggregation in vivo. Mutational and pH normalization analyses indicated that the channel's H+ conductance is essential for normal lysosome function. Thus, modulation of LyPAP by cellular cues may dynamically tune the pH optima of endosomes and lysosomes to regulate lysosomal degradation and PD pathology.
    Keywords:  Proton channel; acidification; degradation; lysosome; pH optimum
    DOI:  https://doi.org/10.1016/j.cell.2022.05.021
  2. J Biol Chem. 2022 Jun 21. pii: S0021-9258(22)00601-9. [Epub ahead of print] 102159
    Impaired Mitophagy in Sanfilippo A mice Causes Hypertriglyceridemia and Brown Adipose Tissue Activation.
    Miguel Tillo, William C Lamanna, Chrissa A Dwyer, Daniel R Sandoval, Ariane R Pessentheiner, Norah Al-Azzam, Stéphane Sarrazin, Jon C Gonzales, Shih-Hsin Kan, Alexander Y Andreyev, Nicholas Schultheis, Bryan E Thacker, Charles A Glass, Patricia I Dickson, Raymond Y Wang, Scott B Selleck, Jeffrey D Esko, Philip L S M Gordts.
      Lysosomal storage diseases result in various developmental and physiological complications, including cachexia. To study the causes for the negative energy balance associated with cachexia, we assessed the impact of sulfamidase deficiency and heparan sulfate storage on energy homeostasis and metabolism in a mouse model of Type IIIa mucopolysaccharidosis (MPS IIIa, Sanfilippo A syndrome). At 12 weeks of age, MPS IIIa mice exhibited fasting and postprandial hypertriglyceridemia compared to wild-type mice, with a reduction of white and brown adipose tissue depots. Partitioning of dietary [3H]triolein showed a marked increase in intestinal uptake and secretion, whereas hepatic production and clearance of triglyceride-rich lipoproteins did not differ from wild-type controls. Uptake of dietary triolein was also elevated in brown adipose tissue (BAT), and notable increases in beige adipose tissue occurred, resulting in hyperthermia, hyperphagia, hyperdipsia, and increased energy expenditure. Furthermore, fasted MPS IIIa mice remained hyperthermic when subjected to low temperature, but became cachexic and profoundly hypothermic when treated with a lipolytic inhibitor. We demonstrated the reliance on increased lipid fueling of BAT was driven by a reduced ability to generate energy from stored lipids within the depot. These alterations arose from impaired autophagosome-lysosome fusion, resulting in increased mitochondria content in beige and BAT. Finally, we show the increased mitochondria content in BAT and postprandial dyslipidemia was partially reversed upon a 5-week treatment with recombinant sulfamidase. We hypothesize that increased BAT activity and persistent increases in energy demand in MPS IIIa mice contribute to the negative energy balance observed in MPS IIIa patients.
    Keywords:  Mucopolysaccharidoses; autophagy; dyslipidemia; hyperthermia; mitochondria; sulfamidase
    DOI:  https://doi.org/10.1016/j.jbc.2022.102159
  3. J Mol Neurosci. 2022 Jun 21.
    Massive Accumulation of Sphingomyelin Affects the Lysosomal and Mitochondria Compartments and Promotes Apoptosis in Niemann-Pick Disease Type A.
    Emma Veronica Carsana, Giulia Lunghi, Simona Prioni, Laura Mauri, Nicoletta Loberto, Alessandro Prinetti, Fabio Andrea Zucca, Rosaria Bassi, Sandro Sonnino, Elena Chiricozzi, Stefano Duga, Letizia Straniero, Rosanna Asselta, Giulia Soldà, Maura Samarani, Massimo Aureli.
      Niemann-Pick type A disease (NPA) is a rare lysosomal storage disorder caused by mutations in the gene coding for the lysosomal enzyme acid sphingomyelinase (ASM). ASM deficiency leads to the consequent accumulation of its uncatabolized substrate, the sphingolipid sphingomyelin (SM), causing severe progressive brain disease. To study the effect of the aberrant lysosomal accumulation of SM on cell homeostasis, we loaded skin fibroblasts derived from a NPA patient with exogenous SM to mimic the levels of accumulation characteristic of the pathological neurons. In SM-loaded NPA fibroblasts, we found the blockage of the autophagy flux and the impairment of the mitochondrial compartment paralleled by the altered transcription of several genes, mainly belonging to the electron transport chain machinery and to the cholesterol biosynthesis pathway. In addition, SM loading induces the nuclear translocation of the transcription factor EB that promotes the lysosomal biogenesis and exocytosis. Interestingly, we obtained similar biochemical findings in the brain of the NPA mouse model lacking ASM (ASMKO mouse) at the neurodegenerative stage. Our work provides a new in vitro model to study NPA etiopathology and suggests the existence of a pathogenic lysosome-plasma membrane axis that with an impairment in the mitochondrial activity is responsible for the cell death.
    Keywords:  Lysosomes; Mitochondria; Niemann-Pick; Plasma membrane; SMPD1; Sphingomyelin
    DOI:  https://doi.org/10.1007/s12031-022-02036-4
  4. Mol Reprod Dev. 2022 Jun 21.
    Borcs6 is required for endo-lysosomal degradation during early development.
    Charlotte J Bell, Neha Gupta, Kimberly D Tremblay, Jesse Mager.
      Early development and differentiation require precise control of cellular functions. Lysosomal degradation is a critical component of normal cellular homeostasis, allowing for degradation of signaling molecules, proteins, and other macromolecules for cellular remodeling and signaling. Little is known about the role of lysosomal function in mammalian embryos before gastrulation. Borcs6 is a protein involved in lysosomal trafficking as well as endo-lysosomal and autophagosome fusion. Here, we show that Borcs6 is necessary for efficient endo-lysosomal degradation in the early embryo. Although embryos lacking Borcs6 are developmentally comparable to control littermates at E5.5, they are characterized by large cells containing increased levels of late endosomes and abnormal nuclei. Furthermore, these embryos display a skewed ratio of extraembryonic and embryonic cell lineages, are delayed by E6.5, and do not undergo normal gastrulation. These results demonstrate the essential functions of lysosomal positioning and fusion with endosomes during early embryonic development and indicate that the early lethality of BORCS6 mutant embryos is primarily due to defects in the HOPS-related function of BORC rather than lysosomal positioning.
    Keywords:  Borcs6; autophagy; development; knockout; lysosome
    DOI:  https://doi.org/10.1002/mrd.23626
  5. Cell Death Differ. 2022 Jun 23.
    Past, present, and future perspectives of transcription factor EB (TFEB): mechanisms of regulation and association with disease.
    Anderson Tan, Renuka Prasad, Chaerin Lee, Eek-Hoon Jho.
      Transcription factor EB (TFEB), a member of the MiT/TFE family of basic helix-loop-helix leucine zipper transcription factors, is an established central regulator of the autophagy/lysosomal-to-nucleus signaling pathway. Originally described as an oncogene, TFEB is now widely known as a regulator of various processes, such as energy homeostasis, stress response, metabolism, and autophagy-lysosomal biogenesis because of its extensive involvement in various signaling pathways, such as mTORC1, Wnt, calcium, and AKT signaling pathways. TFEB is also implicated in various human diseases, such as lysosomal storage disorders, neurodegenerative diseases, cancers, and metabolic disorders. In this review, we present an overview of the major advances in TFEB research over the past 30 years, since its description in 1990. This review also discusses the recently discovered regulatory mechanisms of TFEB and their implications for human diseases. We also summarize the moonlighting functions of TFEB and discuss future research directions and unanswered questions in the field. Overall, this review provides insight into our understanding of TFEB as a major molecular player in human health, which will take us one step closer to promoting TFEB from basic research into clinical and regenerative applications.
    DOI:  https://doi.org/10.1038/s41418-022-01028-6
  6. Angew Chem Int Ed Engl. 2022 Jun 22.
    Lysosome Interference Enabled by Proton-Driven Dynamic Assembly of DNA Nanoframework inside Cells.
    Yuhang Dong, Feng Li, Zhaoyue Lv, Shuai Li, Meihe Yuan, Nachuan Song, Jinqiao Liu, Dayong Yang.
      Developing material chemistry systems coupled with biological processes is a promising way to rationally modulate lysosomal functions. Herein, we report a proton-driven dynamic assembly of DNA nanoframework inside cells coupled with the lysosome-mediated endocytosis pathways/lysosomal maturation, achieving the rational modulation of lysosomal functions, which we termed as lysosome interference. Through lysosome-mediated endocytosis, DNA nanoframework with acid-responsive semi-i-motif entered into lysosome and assembled into aggregate triggered by lysosomal acidity, which performed a long-term retention. Meanwhile, the consumption of protons resulted in lysosomal acidity reduction and hydrolase activity attenuation, thereby alleviating the degradation of nucleic acid drugs in interfered lysosomes and improving gene silencing effect. This study explores a new avenue to achieve lysosome interference by coupling subcellular microenvironment and precisely-programmable assembly system.
    Keywords:  DNA nanostructures; DNA nanotechnology; dynamic assembly; lysosome interference
    DOI:  https://doi.org/10.1002/anie.202207770
  7. Autophagy. 2022 Jun 19.
    Targeted protein degradation via the autophagy-lysosome system: AUTOTAC (AUTOphagy-TArgeting Chimera).
    Chang Hoon Ji, Min Ju Lee, Hee Yeon Kim, Ah Jung Heo, Daniel Youngjae Park, Yun Kyung Kim, Bo Yeon Kim, Yong Tae Kwon.
      Targeted protein degradation allows targeting undruggable proteins for therapeutic applications as well as eliminating proteins of interest for research purposes. While several types of degraders that harness the proteasome or the lysosome have been developed, a technology that simultaneously degrades targets and accelerates cellular autophagic flux remains unavailable. In this study, we developed a general chemical tool by which given intracellular proteins are targeted to macroautophagy for lysosomal degradation. This platform technology, termed AUTOTAC (AUTOphagy-TArgeting Chimera), employs bifunctional molecules composed of target-binding ligands (TBLs) linked to autophagy-targeting ligands (ATLs). Upon binding to targets via the TBL, the ATL binds the ZZ domain of the otherwise dormant autophagy receptor SQSTM1/p62 (sequestosome 1), which activates SQSTM1 associated with targets and sequesters them into oligomeric species for autophagic targeting and lysosomal degradation. AUTOTACs were used to degrade various oncoproteins or aggregation-prone proteins in neurodegeneration both in vitro and/or in vivo. We suggest that AUTOTAC provides a platform for selective proteolysis as a research tool and in drug development.
    Keywords:  N-degron pathway; N-terminal arginylation; SQSTM1/p62; chemical tools; neurodegeneration; protein quality control; proteinopathy; proteolysis; selective autophagy; targeted protein degradation (TPD)
    DOI:  https://doi.org/10.1080/15548627.2022.2091338
  8. Proc Natl Acad Sci U S A. 2022 Jun 28. 119(26): e2111506119
    Glycan degradation promotes macroautophagy.
    Alice D Baudot, Victoria M-Y Wang, Josh D Leach, Jim O'Prey, Jaclyn S Long, Viola Paulus-Hock, Sergio Lilla, David M Thomson, John Greenhorn, Farah Ghaffar, Colin Nixon, Miep H Helfrich, Douglas Strathdee, Judith Pratt, Francesco Marchesi, Sara Zanivan, Kevin M Ryan.
      Macroautophagy promotes cellular homeostasis by delivering cytoplasmic constituents to lysosomes for degradation [Mizushima, Nat. Cell Biol. 20, 521-527 (2018)]. However, while most studies have focused on the mechanisms of protein degradation during this process, we report here that macroautophagy also depends on glycan degradation via the glycosidase, α-l-fucosidase 1 (FUCA1), which removes fucose from glycans. We show that cells lacking FUCA1 accumulate lysosomal glycans, which is associated with impaired autophagic flux. Moreover, in a mouse model of fucosidosis-a disease characterized by inactivating mutations in FUCA1 [Stepien et al., Genes (Basel) 11, E1383 (2020)]-glycan and autophagosome/autolysosome accumulation accompanies tissue destruction. Mechanistically, using lectin capture and mass spectrometry, we identified several lysosomal enzymes with altered fucosylation in FUCA1-null cells. Moreover, we show that the activity of some of these enzymes in the absence of FUCA1 can no longer be induced upon autophagy stimulation, causing retardation of autophagic flux, which involves impaired autophagosome-lysosome fusion. These findings therefore show that dysregulated glycan degradation leads to defective autophagy, which is likely a contributing factor in the etiology of fucosidosis.
    Keywords:  fucosidosis; lysosomes; macroautophagy; α-l-fucosidase 1
    DOI:  https://doi.org/10.1073/pnas.2111506119
  9. Front Mol Neurosci. 2022 ;15 872407
    Functional Characterization of CLCN4 Variants Associated With X-Linked Intellectual Disability and Epilepsy.
    Raul E Guzman, Juan Sierra-Marquez, Stefanie Bungert-Plümke, Arne Franzen, Christoph Fahlke.
      Early/late endosomes, recycling endosomes, and lysosomes together form the endo-lysosomal recycling pathway. This system plays a crucial role in cell differentiation and survival, and dysregulation of the endo-lysosomal system appears to be important in the pathogenesis of neurodevelopmental and neurodegenerative diseases. Each endo-lysosomal compartment fulfils a specific function, which is supported by ion transporters and channels that modify ion concentrations and electrical gradients across endo-lysosomal membranes. CLC-type Cl-/H+ exchangers are a group of endo-lysosomal transporters that are assumed to regulate luminal acidification and chloride concentration in multiple endosomal compartments. Heterodimers of ClC-3 and ClC-4 localize to various internal membranes, from the endoplasmic reticulum and Golgi to recycling endosomes and late endosomes/lysosomes. The importance of ClC-4-mediated ion transport is illustrated by the association of naturally occurring CLCN4 mutations with epileptic encephalopathy, intellectual disability, and behavioral disorders in human patients. However, how these mutations affect the expression, subcellular localization, and function of ClC-4 is insufficiently understood. We here studied 12 CLCN4 variants that were identified in patients with X-linked intellectual disability and epilepsy and were already characterized to some extent in earlier work. We analyzed the consequences of these mutations on ClC-4 ion transport, subcellular trafficking, and heterodimerization with ClC-3 using heterologous expression in mammalian cells, biochemistry, confocal imaging, and whole-cell patch-clamp recordings. The mutations led to a variety of changes in ClC-4 function, ranging from gain/loss of function and impaired heterodimerization with ClC-3 to subtle impairments in transport functions. Our results suggest that even slight functional changes to the endosomal Cl-/H+ exchangers can cause serious neurological symptoms.
    Keywords:  CLCN4; chloride-proton exchanger; intellectual disability; ion channels and epilepsy; patch clamp
    DOI:  https://doi.org/10.3389/fnmol.2022.872407
  10. Cells. 2022 Jun 20. pii: 1977. [Epub ahead of print]11(12):
    Age-Related Lysosomal Dysfunctions.
    Lena Guerrero-Navarro, Pidder Jansen-Dürr, Maria Cavinato.
      Organismal aging is normally accompanied by an increase in the number of senescent cells, growth-arrested metabolic active cells that affect normal tissue function. These cells present a series of characteristics that have been studied over the last few decades. The damage in cellular organelles disbalances the cellular homeostatic processes, altering the behavior of these cells. Lysosomal dysfunction is emerging as an important factor that could regulate the production of inflammatory molecules, metabolic cellular state, or mitochondrial function.
    Keywords:  aging; lysosome; senescence
    DOI:  https://doi.org/10.3390/cells11121977
  11. Front Cell Dev Biol. 2022 ;10 843079
    Unexpected Phenotype Reversion and Survival in a Zebrafish Model of Multiple Sulfatase Deficiency.
    Angeleen Fleming, Low Zhe Xuan, Gentzane Sanchez-Elexpuru, Sarah V Williams, Dylan Windell, Michael H Gelb, Zackary M Herbst, Lars Schlotawa, David C Rubinsztein.
      Multiple sulfatase deficiency (MSD) is a rare recessively inherited Mendelian disorder that manifests with developmental delay, neurodegeneration, skeletal deformities, facial dysmorphism, congenital growth retardation, and other clinical signs. The disorder is caused by mutations in the SUMF1 gene, which encodes the formylglycine-generating enzyme (FGE), and responsible for the activation of sulfatases. Mutations in SUMF1 result in reduced or absent FGE function with consequent compromised activities of its client sulfatases. This leads to an accumulation of enzyme substrates, such as glycosaminoglycans and sulfolipids, within lysosomes and subsequently impaired lysosome function and cellular pathology. Currently, there are no disease modifying therapeutic options for MSD patients, hence the need for more suitable animal models to investigate the disorder. Here, we describe the characterisation of a sumf1 null zebrafish model, which has negligible sulfatase activity. Our sumf1 -/- zebrafish model successfully recapitulates the pathology of MSD such as cranial malformation, altered bone development, an enlarged population of microglia, and growth retardation during early development but lacks early lethality of mouse Sumf1 -/- models. Notably, we provide evidence of recovery in MSD pathology during later developmental stages, resulting in homozygous mutants that are viable. Hence, our data suggest the possibility of a unique compensatory mechanism that allows the sumf1 -/- null zebrafish to survive better than human MSD patients and mouse Sumf1 -/- models.
    Keywords:  SUMF1; formylglycine-generating enzyme; lysosome; multiple sulfatase deficiency; zebrafish
    DOI:  https://doi.org/10.3389/fcell.2022.843079
  12. Biomolecules. 2022 Jun 08. pii: 802. [Epub ahead of print]12(6):
    The Translational Regulation in mTOR Pathway.
    Miaomiao Yang, Yanming Lu, Weilan Piao, Hua Jin.
      The mechanistic/mammalian target of rapamycin (mTOR) plays a master role in cell proliferation and growth in response to insulin, amino acids, energy levels, and oxygen. mTOR can coordinate upstream signals with downstream effectors, including transcriptional and translational apparatuses to regulate fundamental cellular processes such as energy utilization, protein synthesis, autophagy, cell growth, and proliferation. Of the above, protein synthesis is highly energy-consuming; thus, mRNA translation is under the tight and immediate control of mTOR signaling. The translational regulation driven by mTOR signaling mainly relies on eukaryotic translation initiation factor 4E (eIF4E)-binding protein (4E-BP), ribosomal protein S6 kinase (S6K), and its downstream players, which are significant in rapid cellular response to environmental change. mTOR signaling not only controls the general mRNA translation, but preferential mRNA translation as well. This means that mTOR signaling shows the stronger selectivity to particular target mRNAs. Some evidence has supported the contribution of 4E-BP and La-related proteins 1 (LARP1) to such translational regulation. In this review, we summarize the mTOR pathway and mainly focus on mTOR-mediated mRNA translational regulation. We introduce the major components of mTOR signaling and their functions in translational control in a general or particular manner, and describe how the specificity of regulation is coordinated. Furthermore, we summarize recent research progress and propose additional ideas for reference. Because the mTOR pathway is on the center of cell growth and metabolism, comprehensively understanding this pathway will contribute to the therapy of related diseases, including cancers, type 2 diabetes, obesity, and neurodegeneration.
    Keywords:  4E-BP; LARP1; S6K; mTOR; translational regulation
    DOI:  https://doi.org/10.3390/biom12060802
  13. J Pharmacol Exp Ther. 2022 Jun 18. pii: JPET-AR-2022-001119. [Epub ahead of print]
    Tralesinidase alfa enzyme replacement therapy prevents disease manifestations in a canine model of mucopolysaccharidosis type IIIB.
    N Matthew Ellinwood, Bethann N Valentine, Andrew S Hess, Jackie K Jens, Elizabeth M Snella, Maryam Jamil, Shannon J Hostetter, Nicholas D Jeffery, Jodi D Smith, Suzanne T Millman, Rebecca L Parsons, Mark T Butt, Sundeep Chandra, Martin T Egeland, Ana B Assis, Hemanth R Nelvagal, Jonathan D Cooper, Igor Nestrasil, Bryon A Mueller, Rene Labounek, Amy Paulson, Heather Prill, Xiao Ying Liu, Huiyu Zhou, Roger Lawrence, Brett E Crawford, Anita Grover, Ganesh Cherala, Andrew C Melton, Anu Cherukuri, Brian R Vuillemenot, Jill Cm Wait, Charles A O'Neill, Jason Pinkstaff, Joseph Kovalchin, Eric Zanelli, Emma McCullagh.
      Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B; OMIM #252920) is a lethal, pediatric, neuropathic, autosomal recessive, and lysosomal storage disease with no approved therapy. Patients are deficient in the activity of N-acetyl-alpha-glucosaminidase (NAGLU; EC 3.2.150), necessary for normal lysosomal degradation of the glycosaminoglycan heparan sulfate (HS). Tralesinidase alfa (TA), a fusion protein comprised of recombinant human NAGLU and a modified human insulin-like growth factor 2, is in development as an enzyme replacement therapy that is administered via intracerebroventricular (ICV) infusion, thus circumventing the blood brain barrier. Previous studies have confirmed ICV infusion results in widespread distribution of TA throughout the brains of mice and non-human primates. We assessed the long-term tolerability, pharmacology, and clinical efficacy of TA in a canine model of MPS IIIB over a 20-month study. Long-term administration of TA was well-tolerated as compared to administration of vehicle. TA was widely distributed across brain regions, which was confirmed in a follow-up 8-week pharmacokinetic/pharmacodynamic study. MPS IIIB dogs treated for up to 20 months had near-normal levels of HS and HS-NRE in CSF and central nervous system (CNS) tissues. TA-treated MPS IIIB dogs performed better on cognitive tests, had improved CNS pathology and decreased cerebellar volume loss relative to vehicle-treated MPS IIIB dogs. These findings demonstrate the ability of TA to prevent or limit the biochemical, pathological, and cognitive manifestations of canine MPS IIIB disease, thus providing support of its potential long-term tolerability and efficacy in MPS IIIB subjects. Significance Statement This work illustrates the efficacy and tolerability of tralesinidase alfa as a potential therapeutic for MPS IIIB patients by documenting that direct CNS administration to MPS IIIB dogs prevents accumulation of disease-associated GAGs in lysosomes, hepatomegaly, cerebellar atrophy, and cognitive decline.
    Keywords:  animal/nonclinical/preclinical; drug development/discovery; pharmacodynamics
    DOI:  https://doi.org/10.1124/jpet.122.001119
  14. Cancer Res. 2022 Jun 24. pii: canres.4403.2021. [Epub ahead of print]
    The central role of mTORC1 in amino acid sensing.
    Shusheng Yue, Guanya Li, Shanping He, Tingting Li.
      The mechanistic target of rapamycin (mTOR) is a master regulator of cell growth that controls cell homeostasis in response to nutrients, growth factors, and other environmental cues. Recent studies have emphasized the importance of lysosomes as a hub for nutrient sensing, especially amino acid sensing by mTORC1. This review highlights recent advances in understanding the amino acid-mTORC1 signaling axis and the role of mTORC1 in cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-4403
  15. Diagnostics (Basel). 2022 Jun 08. pii: 1414. [Epub ahead of print]12(6):
    Quantitation of a Urinary Profile of Biomarkers in Gaucher Disease Type 1 Patients Using Tandem Mass Spectrometry.
    Iskren Menkovic, Michel Boutin, Abdulfatah Alayoubi, Filipa Curado, Peter Bauer, François E Mercier, Christiane Auray-Blais.
      Gaucher disease is a rare inherited disorder caused by a deficiency of the lysosomal acid beta-glucocerebrosidase enzyme. Metabolomic studies by our group targeted several new potential urinary biomarkers. Apart from lyso-Gb1, these studies highlighted lyso-Gb1 analogs -28, -26, -12 (A/B), +2, +14, +16 (A/B), +30, and +32 Da, and polycyclic lyso-Gb1 analogs 362, 366, 390, and 394 Da. The main objective of the current study was to develop and validate a robust UPLC-MS/MS method to study the urine distribution of these biomarkers in patients.
    METHOD: Urine samples were purified using solid-phase extraction. A 12 min UPLC-MS/MS method was developed.
    RESULTS: Validation assays revealed high precision and accuracy for creatinine and lyso-Gb1. Most lyso-Gb1 analogs had good recovery rates and high intra- and interday precision assays. Biomarker-estimated LOD and LOQ levels ranged from 56-109 pM to 186-354 pM, respectively. Comparison between GD patients and healthy controls showed significant differences in most biomarker levels. Typically, treated GD patients presented lower biomarker levels compared to untreated patients.
    CONCLUSIONS: These data suggest that the metabolites investigated might be interesting GD biomarkers. More studies with a larger cohort of patients will be needed to better understand the clinical significance of these GD biomarkers.
    Keywords:  Gaucher disease type 1; biomarkers; glucosylsphingosine; lyso-Gb1; lyso-Gb1 analogs; polycyclic lyso-Gb1 analogs; tandem mass spectrometry; ultra-performance liquid chromatography; urine
    DOI:  https://doi.org/10.3390/diagnostics12061414
  16. Curr Biol. 2022 Jun 20. pii: S0960-9822(22)00707-2. [Epub ahead of print]32(12): R684-R696
    Balancing nutrient and energy demand and supply via autophagy.
    Congcong He.
      Maintaining nutrient and energy homeostasis is crucial for the survival and function of cells and organisms in response to environmental stress. Cells have evolved a stress-induced catabolic pathway, termed autophagy, to adapt to stress conditions such as starvation. During autophagy, damaged or non-essential cellular structures are broken down in lysosomes, and the resulting metabolites are reused for core biosynthetic processes or energy production. Recent studies have revealed that autophagy can target and degrade different types of nutrient stores and produce a variety of metabolites and fuels, including amino acids, nucleotides, lipids and carbohydrates. Here, we will focus on how autophagy functions to balance cellular nutrient and energy demand and supply - specifically, how energy deprivation switches on autophagic catabolism, how autophagy halts anabolism by degrading the protein synthesis machinery, and how bulk and selective autophagy-derived metabolites recycle and feed into a variety of bioenergetic and anabolic pathways during stress conditions. Recent new insights and progress in these areas provide a better understanding of how resource mobilization and reallocation sustain essential metabolic and anabolic activities under unfavorable conditions.
    DOI:  https://doi.org/10.1016/j.cub.2022.04.071
  17. Pharmaceutics. 2022 Jun 11. pii: 1240. [Epub ahead of print]14(6):
    Treatment of Neuronopathic Mucopolysaccharidoses with Blood-Brain Barrier-Crossing Enzymes: Clinical Application of Receptor-Mediated Transcytosis.
    Hiroyuki Sonoda, Kenichi Takahashi, Kohtaro Minami, Toru Hirato, Tatsuyoshi Yamamoto, Sairei So, Kazunori Tanizawa, Mathias Schmidt, Yuji Sato.
      Enzyme replacement therapy (ERT) has paved the way for treating the somatic symptoms of lysosomal storage diseases (LSDs), but the inability of intravenously administered enzymes to cross the blood-brain barrier (BBB) has left the central nervous system (CNS)-related symptoms of LSDs largely impervious to the therapeutic benefits of ERT, although ERT via intrathecal and intracerebroventricular routes can be used for some neuronopathic LSDs (in particular, mucopolysaccharidoses). However, the considerable practical issues involved make these routes unsuitable for long-term treatment. Efforts have been made to modify enzymes (e.g., by fusing them with antibodies against innate receptors on the cerebrovascular endothelium) so that they can cross the BBB via receptor-mediated transcytosis (RMT) and address neuronopathy in the CNS. This review summarizes the various scientific and technological challenges of applying RMT to the development of safe and effective enzyme therapeutics for neuronopathic mucopolysaccharidoses; it then discusses the translational and methodological issues surrounding preclinical and clinical evaluation to establish RMT-applied ERT.
    Keywords:  blood–brain barrier; enzyme replacement therapy; insulin receptor; lysosomal storage disease; neurodegeneration; neuronopathic mucopolysaccharidosis; receptor-mediated transcytosis; transferrin receptor
    DOI:  https://doi.org/10.3390/pharmaceutics14061240
  18. Am J Physiol Endocrinol Metab. 2022 Jun 20.
    Novel roles of mTORC2 in regulation of insulin secretion by actin filament remodeling.
    Manuel Blandino-Rosano, Joshua O Scheys, Joao Pedro Werneck-de-Castro, Ruy A Louzada, Joana Almaca, Gil Leibowitz, Markus A Ruegg, Michael N Hall, Ernesto Bernal-Mizrachi.
      Mammalian target of rapamycin (mTOR) kinase is an essential hub where nutrients and growth factors converge to control cellular metabolism. mTOR interacts with different accessory proteins to form complexes 1 and 2 (mTORC); and each complex has different intracellular targets. Although mTORC1 role in β-cells has been extensively studied, less is known about mTORC2 function in β-cells. Here we show that mice with constitutive and inducible β-cell specific deletion of RICTOR (βRicKO and iβRicKO mice, respectively) are glucose intolerant due to impaired insulin secretion when glucose is injected intraperitoneally. Decreased insulin secretion in βRicKO islets was caused by abnormal actin polymerization. Interestingly, when glucose was administered orally, no difference in glucose homeostasis and insulin secretion were observed, suggesting that incretins are counteracting the mTOC2 deficiency. Mechanistically, glucagon-like peptide-1 (GLP-1), but not gastric inhibitory polypeptide (GIP), rescued insulin secretion in vivo and in vitro by improving actin polymerization in βRicKO islets. In conclusion, mTORC2 regulates glucose-stimulates insulin secretion by promoting actin filament remodeling.
    Keywords:  Actin Remodeling; Incretins; Insulin Secretion; Rictor; mTORC2
    DOI:  https://doi.org/10.1152/ajpendo.00076.2022
  19. J Hazard Mater. 2022 May 15. pii: S0304-3894(22)00271-0. [Epub ahead of print]430 128483
    TFEB ameliorates autophagy flux disturbance induced by PBDE-47 via up-regulating autophagy-lysosome fusion.
    Huayang Tang, Haoying Huang, Dan Wang, Pei Li, Zhiyuan Tian, Dongjie Li, Sumei Wang, Rulin Ma, Tao Xia, Aiguo Wang.
      2,2',4,4'-tetrabromodiphenyl ether (PBDE-47), the widely used brominated flame retardant, has remarkable neurotoxicity which is associated with autophagy disorder. However, the mechanism remains unclear. The results showed that PBDE-47 damaged lysosomal biogenesis and interfered with autophagy-lysosome fusion both in vivo and in vitro. Our investigation further demonstrated that PBDE-47 could downregulate TFEB expression and inhibit the nuclear translocation of TFEB. Knockdown of TFEB in PC12 cells increased the reduction of lysosomal-associated proteins and the expression of STX17-SNAP29-VAMP8 proteins involved in autophagy-lysosomal fusion. Conversely, Overexpression TFEB in vitro significantly improved lysosomal abundance and ameliorated the autophagosome-lysosome fusion inhibition, thus restoring autophagic flux and improving PC12 cells survival. In addition, TFEB biologically interacted with STX17 by not inducing or inducing TFEB overexpression. Collectively, our results indicate that the autophagy flux compromised by PBDE-47 is related to the defective fusion of autophagosome and lysosome. TFEB may serve as a promising molecular target for future study of PBDE-47 developmental neurotoxicity.
    Keywords:  2,2′,4,4′-tetrabromodiphenyl ether; Autophagosome-lysosome fusion; Neurotoxicity; STX17; Transcription factor EB
    DOI:  https://doi.org/10.1016/j.jhazmat.2022.128483
  20. Nat Metab. 2022 Jun 20.
    A YAP/TAZ-TEAD signalling module links endothelial nutrient acquisition to angiogenic growth.
    Yu Ting Ong, Jorge Andrade, Max Armbruster, Chenyue Shi, Marco Castro, Ana S H Costa, Toshiya Sugino, Guy Eelen, Barbara Zimmermann, Kerstin Wilhelm, Joseph Lim, Shuichi Watanabe, Stefan Guenther, Andre Schneider, Francesca Zanconato, Manuel Kaulich, Duojia Pan, Thomas Braun, Holger Gerhardt, Alejo Efeyan, Peter Carmeliet, Stefano Piccolo, Ana Rita Grosso, Michael Potente.
      Angiogenesis, the process by which endothelial cells (ECs) form new blood vessels from existing ones, is intimately linked to the tissue's metabolic milieu and often occurs at nutrient-deficient sites. However, ECs rely on sufficient metabolic resources to support growth and proliferation. How endothelial nutrient acquisition and usage are regulated is unknown. Here we show that these processes are instructed by Yes-associated protein 1 (YAP)/WW domain-containing transcription regulator 1 (WWTR1/TAZ)-transcriptional enhanced associate domain (TEAD): a transcriptional module whose function is highly responsive to changes in the tissue environment. ECs lacking YAP/TAZ or their transcriptional partners, TEAD1, 2 and 4 fail to divide, resulting in stunted vascular growth in mice. Conversely, activation of TAZ, the more abundant paralogue in ECs, boosts proliferation, leading to vascular hyperplasia. We find that YAP/TAZ promote angiogenesis by fuelling nutrient-dependent mTORC1 signalling. By orchestrating the transcription of a repertoire of cell-surface transporters, including the large neutral amino acid transporter SLC7A5, YAP/TAZ-TEAD stimulate the import of amino acids and other essential nutrients, thereby enabling mTORC1 activation. Dissociating mTORC1 from these nutrient inputs-elicited by the loss of Rag GTPases-inhibits mTORC1 activity and prevents YAP/TAZ-dependent vascular growth. Together, these findings define a pivotal role for YAP/TAZ-TEAD in controlling endothelial mTORC1 and illustrate the essentiality of coordinated nutrient fluxes in the vasculature.
    DOI:  https://doi.org/10.1038/s42255-022-00584-y
  21. Biology (Basel). 2022 Jun 19. pii: 931. [Epub ahead of print]11(6):
    Role of mTOR Signaling Cascade in Epidermal Morphogenesis and Skin Barrier Formation.
    Juan Wang, Sabine A Eming, Xiaolei Ding.
      The skin epidermis, with its capacity for lifelong self-renewal and rapid repairing response upon injury, must maintain an active status in metabolism. Mechanistic target of rapamycin (mTOR) signaling is a central controller of cellular growth and metabolism that coordinates diverse physiological and pathological processes in a variety of tissues and organs. Recent evidence with genetic mouse models highlights an essential role of the mTOR signaling network in epidermal morphogenesis and barrier formation. In this review, we focus on the recent advances in understanding how mTOR signaling networks, including upstream inputs, kinases and downstream effectors, regulate epidermal morphogenesis and skin barrier formation. Understanding the details of the metabolic signaling will be critical for the development of novel pharmacological approaches to promote skin barrier regeneration and to treat epidermal barrier defect-associated diseases.
    Keywords:  epidermal morphogenesis; epidermis; mTOR; mouse models; skin barrier
    DOI:  https://doi.org/10.3390/biology11060931
  22. Int J Mol Sci. 2022 Jun 18. pii: 6808. [Epub ahead of print]23(12):
    LRRK2 and Proteostasis in Parkinson's Disease.
    María Dolores Pérez-Carrión, Inmaculada Posadas, Javier Solera, Valentín Ceña.
      Parkinson's disease is a neurodegenerative condition initially characterized by the presence of tremor, muscle stiffness and impaired balance, with the deposition of insoluble protein aggregates in Lewy's Bodies the histopathological hallmark of the disease. Although different gene variants are linked to Parkinson disease, mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are one of the most frequent causes of Parkinson's disease related to genetic mutations. LRRK2 toxicity has been mainly explained by an increase in kinase activity, but alternative mechanisms have emerged as underlying causes for Parkinson's disease, such as the imbalance in LRRK2 homeostasis and the involvement of LRRK2 in aggregation and spreading of α-synuclein toxicity. In this review, we recapitulate the main LRRK2 pathological mutations that contribute to Parkinson's disease and the different cellular and therapeutic strategies devised to correct LRRK2 homeostasis. In this review, we describe the main cellular control mechanisms that regulate LRRK2 folding and aggregation, such as the chaperone network and the protein-clearing pathways such as the ubiquitin-proteasome system and the autophagic-lysosomal pathway. We will also address the more relevant strategies to modulate neurodegeneration in Parkinson's disease through the regulation of LRRK2, using small molecules or LRRK2 silencing.
    Keywords:  LRRK2; LRRK2 silencing; Parkinson’s disease; autophagy; chaperones; proteostasis; α-synuclein
    DOI:  https://doi.org/10.3390/ijms23126808
  23. JCI Insight. 2022 Jun 23. pii: e150461. [Epub ahead of print]
    A compound directed against S6K1 hampers fat mass expansion and mitigates diet-induced hepatosteatosis.
    Aina Lluch, Sonia R Veiga, Jèssica Latorre, José M Moreno-Navarrete, Núria Bonifaci, Van Dien Nguyen, You Zhou, Marcus Horing, Gerhard Liebisch, Vesa M Olkkonen, David Llobet-Navas, George Thomas, Ruth Rodriguez-Barrueco, José M Fernández-Real, Sara C Kozma, Francisco J Ortega.
      The ribosomal protein S6 kinase 1 (S6K1) is a relevant effector downstream the mammalian target of rapamycin complex 1 (mTORC1), best known for its role in the control of lipid homeostasis. Consistent with this, mice lacking the S6k1 gene have a defect in their ability to induce the commitment of fat precursor cells to the adipogenic lineage, which contributes to a significant reduction of fat mass. Here, we assess the therapeutic blockage of S6K1 in diet-induced obese mice challenged with LY2584702 tosylate, a specific oral S6K1 inhibitor initially developed for the treatment of solid tumours. We show that diminished S6K1 activity hampers fat mass expansion and ameliorates dyslipidaemia and hepatic steatosis, while modifying transcriptome-wide gene expression programs relevant for adipose and liver function. Accordingly, impaired mTORC1 signalling in fat (decreased) and liver (increased) co-segregated with defective epithelial-mesenchymal transition, being prominent the decreased expression of Cd36 (coding for a fatty acid translocase) and Lgals1 (Galectin 1) in both tissues. All these factors combined align with reduced adipocyte size and improved lipidomic signatures in the liver, while hepatic steatosis and hypertriglyceridemia were improved in treatments lasting either 3 months or 6 weeks.
    Keywords:  Adipose tissue; Metabolism; Obesity; Pharmacology; Therapeutics
    DOI:  https://doi.org/10.1172/jci.insight.150461
  24. Autophagy. 2022 Jun 19. 1-27
    Proteasomal inhibition preferentially stimulates lysosome activity relative to autophagic flux in primary astrocytes.
    Ruiyi Yuan, Younghee Hahn, Max H Stempel, David K Sidibe, Olivia Laxton, Jessica Chen, Aditi Kulkarni, Sandra Maday.
      Neurons and astrocytes face unique demands on their proteome to enable proper function and survival of the nervous system. Consequently, both cell types are critically dependent on robust quality control pathways such as macroautophagy (hereafter referred to as autophagy) and the ubiquitin-proteasome system (UPS). We previously reported that autophagy is differentially regulated in astrocytes and neurons in the context of metabolic stress, but less is understood in the context of proteotoxic stress induced by inhibition of the UPS. Dysfunction of the proteasome or autophagy has been linked to the progression of various neurodegenerative diseases. Therefore, in this study, we explored the connection between autophagy and the proteasome in primary astrocytes and neurons. Prior studies largely in non-neural models report a compensatory relationship whereby inhibition of the UPS stimulates autophagy. To our surprise, inhibition of the proteasome did not robustly upregulate autophagy in astrocytes or neurons. In fact, the effects on autophagy are modest particularly in comparison to paradigms of metabolic stress. Rather, we find that UPS inhibition in astrocytes induces formation of Ub-positive aggregates that harbor the selective autophagy receptor, SQSTM1/p62, but these structures were not productive substrates for autophagy. By contrast, we observed a significant increase in lysosomal degradation in astrocytes in response to UPS inhibition, but this stimulation was not sufficient to reduce total SQSTM1 levels. Last, UPS inhibition was more toxic in neurons compared to astrocytes, suggesting a cell type-specific vulnerability to proteotoxic stress.Abbreviations: Baf A1: bafilomycin A1; CQ: chloroquine; Epox: epoxomicin; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; p-ULK1: phospho-ULK1; SQSTM1/p62: sequestosome 1; Ub: ubiquitin; ULK1: unc-51 like kinase 1; UPS: ubiquitin-proteasome system.
    Keywords:  Astrocytes; LC3; SQSTM1; autophagy; lysosomes; neurons; proteasome; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2022.2084884
  25. Membranes (Basel). 2022 Jun 19. pii: 633. [Epub ahead of print]12(6):
    The ESCRT Machinery: Remodeling, Repairing, and Sealing Membranes.
    Yolanda Olmos.
      The ESCRT machinery is an evolutionarily conserved membrane remodeling complex that is used by the cell to perform reverse membrane scission in essential processes like protein degradation, cell division, and release of enveloped retroviruses. ESCRT-III, together with the AAA ATPase VPS4, harbors the main remodeling and scission function of the ESCRT machinery, whereas early-acting ESCRTs mainly contribute to protein sorting and ESCRT-III recruitment through association with upstream targeting factors. Here, we review recent advances in our understanding of the molecular mechanisms that underlie membrane constriction and scission by ESCRT-III and describe the involvement of this machinery in the sealing and repairing of damaged cellular membranes, a key function to preserve cellular viability and organellar function.
    Keywords:  ESCRT; lysosome; membrane repair; membrane scission; membrane sealing; nuclear envelope; reverse topology
    DOI:  https://doi.org/10.3390/membranes12060633
  26. J Lipid Res. 2022 Jun 17. pii: S0022-2275(22)00076-1. [Epub ahead of print] 100243
    Sorting Through the Extensive and Confusing Roles of Sortilin in Metabolic Disease.
    Kelly A Mitok, Mark P Keller, Alan D Attie.
      Sortilin is a post-Golgi trafficking receptor homologous to the yeast vacuolar protein sorting receptor 10 (VPS10). The VPS10 motif on sortilin is a 10-bladed β-propeller structure capable of binding > 50 proteins covering a wide range of biological functions, including lipid and lipoprotein metabolism, neuronal growth and death, inflammation, and lysosomal degradation. Sortilin has a complex cellular trafficking itinerary, functioning as a receptor in the trans-Golgi network, endosomes, secretory vesicles, multivesicular bodies, and at the cell surface. In addition, sortilin is associated with hypercholesterolemia, Alzheimer's Disease, prion diseases, Parkinson's Disease, and inflammation syndromes. The 1p13.3 locus containing SORT1, the gene encoding sortilin, carries the strongest association with LDL-C of all loci in human genome-wide association studies (GWAS). However, the mechanism by which sortilin influences LDL-C is unclear. Here, we review the role sortilin plays in cardiovascular and metabolic disease and describe in detail the large and often contradictory literature on the role of sortilin in the regulation of LDL cholesterol levels.
    Keywords:  Cholesterol/Metabolism; Cholesterol/Trafficking; Dyslipidemias; LDL/Metabolism; Lipoproteins/Metabolism; SORT1; Sortilin; VPS10; cardiovascular disease; cellular trafficking
    DOI:  https://doi.org/10.1016/j.jlr.2022.100243
  27. Curr Biol. 2022 Jun 20. pii: S0960-9822(22)00711-4. [Epub ahead of print]32(12): R574-R577
    Autophagy: Identification of MTMR5 as a neuron-enriched suppressor.
    Maria Chalokh Vogel, Sandra Maday.
      A puzzle of autophagy in neurons is that, unlike in other cells, it is not robustly induced by inhibition of mammalian target of rapamycin (mTOR). A new study now solves this conundrum and establishes that myotubularin-related phosphatase 5 limits the induction of neuronal autophagy by mTOR inhibitors.
    DOI:  https://doi.org/10.1016/j.cub.2022.04.075
  28. FEBS Open Bio. 2022 Jun 24.
    PF-06409577 inhibits renal cyst progression by concurrently inhibiting the mTOR pathway and CFTR channel activity.
    Limin Su, Haoxing Yuan, Haoran Zhang, Ruoqi Wang, Kequan Fu, Long Yin, Ying Ren, Hongli Liu, Qian Fang, Junqi Wang, Dong Guo.
      Renal cyst development and expansion in autosomal dominant polycystic kidney disease (ADPKD) involves over-proliferation of cyst-lining epithelial cells and excessive cystic fluid secretion. While metformin effectively inhibits renal cyst growth in mouse models of ADPKD it exhibits low potency, and thus an AMPK activator with higher potency is required. Herein, we adopted a drug repurposing strategy to explore the potential of PF-06409577, an adenosine monophosphate-activated protein kinase (AMPK) activator for diabetic nephropathy, in cellular, ex vivo and in vivo models of ADPKD. Our results demonstrated that PF-06409577 effectively down-regulated mammalian target of rapamycin (mTOR) pathway-mediated proliferation of cyst-lining epithelial cells and reduced cystic fibrosis transmembrane conductance regulator (CFTR)-regulated cystic fluid secretion. Overall, our data suggest that PF-06409577 holds therapeutic potential for ADPKD treatment.
    Keywords:  ADPKD; AMPK; CFTR; PF-06409577; kidney disease; mTOR; renal cyst
    DOI:  https://doi.org/10.1002/2211-5463.13459
  29. Fac Rev. 2022 ;11 12
    ConducTORs of a Signaling Symphony: Metabolic and Hormone Responses Converge on TOR and EIN2 in plants.
    Jacob O Brunkard, Caren Chang, Bruce J Mayer, Christian Meyer, Jen Sheen.
      Development is coordinated by dozens of signals that act in overlapping pathways to orchestrate multicellular growth. Understanding how signaling pathways intersect and diverge at a molecular level is critical to predicting how organisms will react to dynamic environmental conditions. In plants, two antagonistic signaling hubs are strictly required to sense and respond to many nutrients and hormones: TARGET OF RAPAMYCIN (TOR) and ETHYLENE INSENSITIVE 2 (EIN2). In this Landmark report, Fu et al. discover that TOR and EIN2 directly interact to choreograph growth and define an unexpected molecular mechanism at the intersection of hormonal and metabolic signaling networks1.
    Keywords:  EIN2; Ethylene; TOR; plants
    DOI:  https://doi.org/10.12703/r-01-000008
  30. Cell. 2022 Jun 23. pii: S0092-8674(22)00648-1. [Epub ahead of print]185(13): 2213-2233.e25
    Cholesterol and matrisome pathways dysregulated in astrocytes and microglia.
    Julia Tcw, Lu Qian, Nina H Pipalia, Michael J Chao, Shuang A Liang, Yang Shi, Bharat R Jain, Sarah E Bertelsen, Manav Kapoor, Edoardo Marcora, Elizabeth Sikora, Elizabeth J Andrews, Alessandra C Martini, Celeste M Karch, Elizabeth Head, David M Holtzman, Bin Zhang, Minghui Wang, Frederick R Maxfield, Wayne W Poon, Alison M Goate.
      The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice. Population and isogenic models demonstrate that APOE4 local haplotype, rather than a single risk allele, contributes to risk. Global transcriptomic analyses reveal human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomal cholesterol sequestration in astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation, and lipid biosynthesis in astrocytes co-cultured with neurons, which recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.
    Keywords:  APOE; Alzheimer; astrocytes; cholesterol; genetic heterogeneity; haplotypes; iPSC disease modeling; inflammation; matrisome; microglia
    DOI:  https://doi.org/10.1016/j.cell.2022.05.017
  31. Cell Death Discov. 2022 Jun 18. 8(1): 293
    An mTOR and DNA-PK dual inhibitor CC-115 hinders non-small cell lung cancer cell growth.
    Fagui Chen, Huasi Zhao, Chenhui Li, Ping Li, Qichuan Zhang.
      Molecularly-targeted agents are still urgently needed for better non-small cell lung cancer (NSCLC) therapy. CC-115 is a potent DNA-dependent protein kinase (DNA-PK) and mammalian target of rapamycin (mTOR) dual blocker. We evaluated its activity in different human NSCLC cells. In various primary human NSCLC cells and A549 cells, CC-115 potently inhibited viability, cell proliferation, cell cycle progression, and hindered cell migration/invasion. Apoptosis was provoked in CC-115-stimulated NSCLC cells. The dual inhibitor, however, was unable to induce significant cytotoxic and pro-apoptotic activity in the lung epithelial cells. In primary NSCLC cells, CC-115 blocked activation of mTORC1/2 and DNA-PK. Yet, CC-115-induced primary NSCLC cell death was more potent than combined inhibition of DNA-PK plus mTOR. Further studies found that CC-115 provoked robust oxidative injury in primary NSCLC cells, which appeared independent of mTOR-DNA-PK dual blockage. In vivo studies showed that CC-115 oral administration in nude mice remarkably suppressed primary NSCLC cell xenograft growth. In CC-115-treated NSCLC xenograft tissues, mTOR-DNA-PK dual inhibition and oxidative injury were detected. Together, CC-115 potently inhibits NSCLC cell growth.
    DOI:  https://doi.org/10.1038/s41420-022-01082-6
  32. Nat Cell Biol. 2022 Jun 23.
    Actin remodelling controls proteasome homeostasis upon stress.
    Thomas David Williams, Roberta Cacioppo, Alexander Agrotis, Ailsa Black, Houjiang Zhou, Adrien Rousseau.
      When cells are stressed, bulk translation is often downregulated to reduce energy demands while stress-response proteins are simultaneously upregulated. To promote proteasome assembly and activity and maintain cell viability upon TORC1 inhibition, 19S regulatory-particle assembly chaperones (RPACs) are selectively translated. However, the molecular mechanism for such selective translational upregulation is unclear. Here, using yeast, we discover that remodelling of the actin cytoskeleton is important for RPAC translation following TORC1 inhibition. mRNA of the RPAC ADC17 is associated with actin cables and is enriched at cortical actin patches under stress, dependent upon the early endocytic protein Ede1. ede1∆ cells failed to induce RPACs and proteasome assembly upon TORC1 inhibition. Conversely, artificially tethering ADC17 mRNA to cortical actin patches enhanced its translation upon stress. These findings suggest that actin-dense structures such as cortical actin patches may serve as a translation platform for a subset of stress-induced mRNAs including regulators of proteasome homeostasis.
    DOI:  https://doi.org/10.1038/s41556-022-00938-4
  33. iScience. 2022 Jun 17. 25(6): 104476
    Pathogenic LRRK2 regulates centrosome cohesion via Rab10/RILPL1-mediated CDK5RAP2 displacement.
    Elena Fdez, Jesús Madero-Pérez, Antonio J Lara Ordóñez, Yahaira Naaldijk, Rachel Fasiczka, Ana Aiastui, Javier Ruiz-Martínez, Adolfo López de Munain, Sally A Cowley, Richard Wade-Martins, Sabine Hilfiker.
      Mutations in LRRK2 increase its kinase activity and cause Parkinson's disease. LRRK2 phosphorylates a subset of Rab proteins which allows for their binding to RILPL1. The phospho-Rab/RILPL1 interaction causes deficits in ciliogenesis and interferes with the cohesion of duplicated centrosomes. We show here that centrosomal deficits mediated by pathogenic LRRK2 can also be observed in patient-derived iPS cells, and we have used transiently transfected cell lines to identify the underlying mechanism. The LRRK2-mediated centrosomal cohesion deficits are dependent on both the GTP conformation and phosphorylation status of the Rab proteins. Pathogenic LRRK2 does not displace proteinaceous linker proteins which hold duplicated centrosomes together, but causes the centrosomal displacement of CDK5RAP2, a protein critical for centrosome cohesion. The LRRK2-mediated centrosomal displacement of CDK5RAP2 requires RILPL1 and phospho-Rab proteins, which stably associate with centrosomes. These data provide fundamental information as to how pathogenic LRRK2 alters the normal physiology of a cell.
    Keywords:  Biological sciences; Cell biology; Cellular neuroscience; Functional aspects of cell biology; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2022.104476
  34. Front Neurol. 2022 ;13 907317
    Promising Effect of High Dose Ambroxol Treatment on Neurocognition and Motor Development in a Patient With Neuropathic Gaucher Disease 2.
    Charlotte Aries, Benjamin Lohmöller, Stephan Tiede, Karolin Täuber, Guido Hartmann, Cornelia Rudolph, Nicole Muschol.
      Gaucher Disease (GD) 2 is a rare inherited lysosomal disorder. Early-onset and rapid progression of neurovisceral symptoms lead to fatal outcome in early childhood. Treatment is symptomatic, a curative therapy is currently not available. This prospective study describes the clinical and biochemical outcome of a GD 2 patient treated with high dose ambroxol from the age of 4 months. Due to progressive hepatosplenomegaly additional enzyme replacement therapy was required 1 year after ambroxol monotherapy was initiated. Detailed clinical follow-up data demonstrated an age-appropriate neurocognitive and motor development but no clear benefit on peripheral organs. Glucosylsphingosine (Lyso-GL1) in cerebrospinal fluid decreased remarkably compared to pre-treatment, whereas Lyso-GL1 and chitotriosidase in blood increased. Ambroxol treatment of patient fibroblasts revealed a significant increase in β-glucocerebrosidase activity in vitro. To our knowledge, this is the first report of a GD 2 patient with age-appropriate cognitive and motor development at 3 years of age. Combination of high dose ambroxol with ERT proved to be a successful approach to manage both visceral and neurological manifestations.
    Keywords:  enzyme replacement therapy; glucocerebrosidase; high dose ambroxol; lysosomal storage disorder; neuropathic Gaucher disease; pharmacological chaperone
    DOI:  https://doi.org/10.3389/fneur.2022.907317
  35. Int J Mol Sci. 2022 Jun 16. pii: 6722. [Epub ahead of print]23(12):
    CRISPR/Cas9-Mediated Constitutive Loss of VCP (Valosin-Containing Protein) Impairs Proteostasis and Leads to Defective Striated Muscle Structure and Function In Vivo.
    Philipp Voisard, Federica Diofano, Amelia A Glazier, Wolfgang Rottbauer, Steffen Just.
      Valosin-containing protein (VCP) acts as a key regulator of cellular protein homeostasis by coordinating protein turnover and quality control. Mutations in VCP lead to (cardio-)myopathy and neurodegenerative diseases such as inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia (IBMPFD) or amyotrophic lateral sclerosis (ALS). To date, due to embryonic lethality, no constitutive VCP knockout animal model exists. Here, we generated a constitutive CRISPR/Cas9-induced vcp knockout zebrafish model. Similar to the phenotype of vcp morphant knockdown zebrafish embryos, we found that vcp-null embryos displayed significantly impaired cardiac and skeletal muscle function. By ultrastructural analysis of skeletal muscle cells and cardiomyocytes, we observed severely disrupted myofibrillar organization and accumulation of inclusion bodies as well as mitochondrial degeneration. vcp knockout was associated with a significant accumulation of ubiquitinated proteins, suggesting impaired proteasomal function. Additionally, markers of unfolded protein response (UPR)/ER-stress and autophagy-related mTOR signaling were elevated in vcp-deficient embryos, demonstrating impaired proteostasis in VCP-null zebrafish. In conclusion, our findings demonstrate the successful generation of a stable constitutive vcp knockout zebrafish line that will enable characterization of the detailed mechanistic underpinnings of vcp loss, particularly the impact of disturbed protein homeostasis on organ development and function in vivo.
    Keywords:  CRISPR/Cas9; VCP; VCPopathies; disease modeling; protein homeostasis; zebrafish
    DOI:  https://doi.org/10.3390/ijms23126722
  36. Front Immunol. 2022 ;13 915906
    Rapamycin Dampens Inflammatory Properties of Bone Marrow ILC2s in IL-33-Induced Eosinophilic Airway Inflammation.
    Emma Boberg, Julie Weidner, Carina Malmhäll, Jenny Calvén, Carmen Corciulo, Madeleine Rådinger.
      The alarmin cytokine interleukin (IL)-33 plays an important proinflammatory role in type 2 immunity and can act on type 2 innate lymphoid cells (ILC2s) and type 2 T helper (TH2) cells in eosinophilic inflammation and asthma. The mechanistic target of rapamycin (mTOR) signaling pathway drives immune responses in several inflammatory diseases, but its role in regulating bone marrow responses to IL-33 is unclear. The aim of this study was to determine the role of the mTORC1 signaling pathway in IL-33-induced bone marrow ILC2 responses and its impact on IL-33-induced eosinophilia. Wild-type mice were intranasally exposed to IL-33 only or in combination with the mTORC1 inhibitor, rapamycin, intraperitoneally. Four groups were included in the study: saline-treated (PBS)+PBS, rapamycin+PBS, PBS+IL-33 and rapamycin+IL-33. Bronchoalveolar lavage fluid (BALF), serum and bone marrow cells were collected and analyzed by differential cell count, enzyme-linked immunosorbent assay and flow cytometry. IL-33 induced phosphorylation of the mTORC1 protein rpS6 in bone marrow ILC2s both ex vivo and in vivo. The observed mTOR signal was reduced by rapamycin treatment, indicating the sensitivity of bone marrow ILC2s to mTORC1 inhibition. IL-5 production by ILC2s was reduced in cultures treated with rapamycin before stimulation with IL-33 compared to IL-33 only. Bone marrow and airway eosinophils were reduced in mice given rapamycin before IL-33-exposure compared to mice given IL-33 only. Bone marrow ILC2s responded to IL-33 in vivo with increased mTORC1 activity and rapamycin treatment successfully decreased IL-33-induced eosinophilic inflammation, possibly by inhibition of IL-5-producing bone marrow ILC2s. These findings highlight the importance of investigating specific cells and proinflammatory pathways as potential drivers of inflammatory diseases, including asthma.
    Keywords:  asthma; bone marrow; eosinophils; innate lymphoid cells; interleukin-33; interleukin-5; mTOR; rapamycin
    DOI:  https://doi.org/10.3389/fimmu.2022.915906
  37. Metabolites. 2022 Jun 08. pii: 527. [Epub ahead of print]12(6):
    Toxic Metabolites and Inborn Errors of Amino Acid Metabolism: What One Informs about the Other.
    Namgyu Lee, Dohoon Kim.
      In inborn errors of metabolism, such as amino acid breakdown disorders, loss of function mutations in metabolic enzymes within the catabolism pathway lead to an accumulation of the catabolic intermediate that is the substrate of the mutated enzyme. In patients of such disorders, dietarily restricting the amino acid(s) to prevent the formation of these catabolic intermediates has a therapeutic or even entirely preventative effect. This demonstrates that the pathology is due to a toxic accumulation of enzyme substrates rather than the loss of downstream products. Here, we provide an overview of amino acid metabolic disorders from the perspective of the 'toxic metabolites' themselves, including their mechanism of toxicity and whether they are involved in the pathology of other disease contexts as well. In the research literature, there is often evidence that such metabolites play a contributing role in multiple other nonhereditary (and more common) disease conditions, and these studies can provide important mechanistic insights into understanding the metabolite-induced pathology of the inborn disorder. Furthermore, therapeutic strategies developed for the inborn disorder may be applicable to these nonhereditary disease conditions, as they involve the same toxic metabolite. We provide an in-depth illustration of this cross-informing concept in two metabolic disorders, methylmalonic acidemia and hyperammonemia, where the pathological metabolites methylmalonic acid and ammonia are implicated in other disease contexts, such as aging, neurodegeneration, and cancer, and thus there are opportunities to apply mechanistic or therapeutic insights from one disease context towards the other. Additionally, we expand our scope to other metabolic disorders, such as homocystinuria and nonketotic hyperglycinemia, to propose how these concepts can be applied broadly across different inborn errors of metabolism and various nonhereditary disease conditions.
    Keywords:  ammonia; hyperammonemia; inborn error of metabolism (IEM); intoxification; metabolism; metabolites; methylmalonic acidemia; toxic metabolites
    DOI:  https://doi.org/10.3390/metabo12060527
  38. Int J Mol Sci. 2022 Jun 16. pii: 6747. [Epub ahead of print]23(12):
    The Inositol Phosphate System-A Coordinator of Metabolic Adaptability.
    Becky Tu-Sekine, Sangwon F Kim.
      All cells rely on nutrients to supply energy and carbon building blocks to support cellular processes. Over time, eukaryotes have developed increasingly complex systems to integrate information about available nutrients with the internal state of energy stores to activate the necessary processes to meet the immediate and ongoing needs of the cell. One such system is the network of soluble and membrane-associated inositol phosphates that coordinate the cellular responses to nutrient uptake and utilization from growth factor signaling to energy homeostasis. In this review, we discuss the coordinated interactions of the inositol polyphosphates, inositol pyrophosphates, and phosphoinositides in major metabolic signaling pathways to illustrate the central importance of the inositol phosphate signaling network in nutrient responses.
    Keywords:  AKT; IP6K; IPMK; OXPHOS; PI3K; glycolysis; inositol polyphosphate; inositol pyrophosphate; insulin; mitochondria
    DOI:  https://doi.org/10.3390/ijms23126747
  39. Nature. 2022 Jun 22.
    eIF5B and eIF1A reorient initiator tRNA to allow ribosomal subunit joining.
    Christopher P Lapointe, Rosslyn Grosely, Masaaki Sokabe, Carlos Alvarado, Jinfan Wang, Elizabeth Montabana, Nancy Villa, Byung-Sik Shin, Thomas E Dever, Christopher S Fraser, Israel S Fernández, Joseph D Puglisi.
      Translation initiation defines the identity and quantity of a synthesized protein. The process is dysregulated in many human diseases1,2. A key commitment step is when the ribosomal subunits join at a translation start site on a messenger RNA to form a functional ribosome. Here, we combined single-molecule spectroscopy and structural methods using an in vitro reconstituted system to examine how the human ribosomal subunits join. Single-molecule fluorescence revealed when the universally conserved eukaryotic initiation factors eIF1A and eIF5B associate with and depart from initiation complexes. Guided by single-molecule dynamics, we visualized initiation complexes that contained both eIF1A and eIF5B using single-particle cryo-electron microscopy. The resulting structure revealed how eukaryote-specific contacts between the two proteins remodel the initiation complex to orient the initiator aminoacyl-tRNA in a conformation compatible with ribosomal subunit joining. Collectively, our findings provide a quantitative and architectural framework for the molecular choreography orchestrated by eIF1A and eIF5B during translation initiation in humans.
    DOI:  https://doi.org/10.1038/s41586-022-04858-z
  40. Sci Adv. 2022 Jun 24. 8(25): eabo5272
    SNARE assembly enlightened by cryo-EM structures of a synaptobrevin-Munc18-1-syntaxin-1 complex.
    Karolina P Stepien, Junjie Xu, Xuewu Zhang, Xiao-Chen Bai, Josep Rizo.
      Munc18-1 forms a template to organize assembly of the neuronal SNARE complex that triggers neurotransmitter release, binding first to a closed conformation of syntaxin-1 where its amino-terminal region interacts with the SNARE motif, and later binding to synaptobrevin. However, the mechanism of SNARE complex assembly remains unclear. Here, we report two cryo-EM structures of Munc18-1 bound to cross-linked syntaxin-1 and synaptobrevin. The structures allow visualization of how syntaxin-1 opens and reveal how part of the syntaxin-1 amino-terminal region can help nucleate interactions between the amino termini of the syntaxin-1 and synaptobrevin SNARE motifs, while their carboxyl termini bind to distal sites of Munc18-1. These observations, together with mutagenesis, SNARE complex assembly experiments, and fusion assays with reconstituted proteoliposomes, support a model whereby these interactions are critical to initiate SNARE complex assembly and multiple energy barriers enable diverse mechanisms for exquisite regulation of neurotransmitter release.
    DOI:  https://doi.org/10.1126/sciadv.abo5272
  41. PLoS Genet. 2022 Jun 21. 18(6): e1010269
    A MademoiseLLE domain binding platform links the key RNA transporter to endosomes.
    Senthil-Kumar Devan, Stephan Schott-Verdugo, Kira Müntjes, Lilli Bismar, Jens Reiners, Eymen Hachani, Lutz Schmitt, Astrid Höppner, Sander Hj Smits, Holger Gohlke, Michael Feldbrügge.
      Spatiotemporal expression can be achieved by transport and translation of mRNAs at defined subcellular sites. An emerging mechanism mediating mRNA trafficking is microtubule-dependent co-transport on shuttling endosomes. Although progress has been made in identifying various components of the endosomal mRNA transport machinery, a mechanistic understanding of how these RNA-binding proteins are connected to endosomes is still lacking. Here, we demonstrate that a flexible MademoiseLLE (MLLE) domain platform within RNA-binding protein Rrm4 of Ustilago maydis is crucial for endosomal attachment. Our structure/function analysis uncovered three MLLE domains at the C-terminus of Rrm4 with a functionally defined hierarchy. MLLE3 recognises two PAM2-like sequences of the adaptor protein Upa1 and is essential for endosomal shuttling of Rrm4. MLLE1 and MLLE2 are most likely accessory domains exhibiting a variable binding mode for interaction with currently unknown partners. Thus, endosomal attachment of the mRNA transporter is orchestrated by a sophisticated MLLE domain binding platform.
    DOI:  https://doi.org/10.1371/journal.pgen.1010269
  42. Mol Cell. 2022 Jun 21. pii: S1097-2765(22)00492-0. [Epub ahead of print]
    Supramolecular assembly of GSK3α as a cellular response to amino acid starvation.
    Laura Hinze, Sabine Schreek, Andre Zeug, Nurul Khalida Ibrahim, Beate Fehlhaber, Lorent Loxha, Buesra Cinar, Evgeni Ponimaskin, James Degar, Connor McGuckin, Gabriela Chiosis, Cornelia Eckert, Gunnar Cario, Beat Bornhauser, Jean-Pierre Bourquin, Martin Stanulla, Alejandro Gutierrez.
      The tolerance of amino acid starvation is fundamental to robust cellular fitness. Asparagine depletion is lethal to some cancer cells, a vulnerability that can be exploited clinically. We report that resistance to asparagine starvation is uniquely dependent on an N-terminal low-complexity domain of GSK3α, which its paralog GSK3β lacks. In response to depletion of specific amino acids, including asparagine, leucine, and valine, this domain mediates supramolecular assembly of GSK3α with ubiquitin-proteasome system components in spatially sequestered cytoplasmic bodies. This effect is independent of mTORC1 or GCN2. In normal cells, GSK3α promotes survival during essential amino acid starvation. In human leukemia, GSK3α body formation predicts asparaginase resistance, and sensitivity to asparaginase combined with a GSK3α inhibitor. We propose that GSK3α body formation provides a cellular mechanism to maximize the catalytic efficiency of proteasomal protein degradation in response to amino acid starvation, an adaptive response co-opted by cancer cells for asparaginase resistance.
    Keywords:  GSK3; Wnt; asparaginase; protein degradation; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1016/j.molcel.2022.05.025
  43. Orphanet J Rare Dis. 2022 06 18. 17(1): 234
    Thirty-year clinical outcomes after haematopoietic stem cell transplantation in neuronopathic Gaucher disease.
    GAUCHERITE Consortium
       BACKGROUND: Neuronopathic Gaucher Disease (nGD) describes the condition of a subgroup of patients with the Lysosomal Storage Disorder (LSD), Gaucher disease with involvement of the central nervous system (CNS) which results from inherited deficiency of β-glucosylceramidase. Although systemic manifestations of disease are now corrected by augmentation with macrophage-targeted therapeutic enzyme (enzyme replacement therapy, ERT), neurological disease progresses unpredictably as a result of failure of therapeutic enzyme to cross the blood-brain barrier (BBB). Without therapy, the systemic and neurological effects of the disease progress and shorten life: investigators, principally in Sweden and the UK, pioneered bone marrow transplantation (BMT; Haematopoietic Stem Cell Transplantation HSCT) to supply healthy marrow-derived macrophages and other cells, to correct the peripheral disease. Here we report the first long-term follow-up (over 20 years in all cases) of nine patients in the UK and Sweden who underwent HSCT in the 1970s and 1980s. This retrospective, multicentre observational study was undertaken to determine whether there are neurological features of Gaucher disease that can be corrected by HSCT and the extent to which deterioration continues after the procedure. Since intravenous administration of ERT is approved for patients with the neuronopathic disease and ameliorates many of the important systemic manifestations but fails to correct the neurological features, we also consider the current therapeutic positioning of HSCT in this disorder.
    RESULTS: In the nine patients here reported, neurological disease continued to progress after transplantation, manifesting as seizures, cerebellar disease and abnormalities of tone and reflexes.
    CONCLUSIONS: Although neurological disease progressed in this cohort of patients, there may be a future role for HSCT in the treatment of nGD. The procedure has the unique advantage of providing a life-long source of normally functioning macrophages in the bone marrow, and possibly other sites, after a single administration. HSCT moreover, clearly ameliorates systemic disease and this may be advantageous-especially where sustained provision of high-cost ERT cannot be guaranteed. Given the remaining unmet needs of patients with neuronopathic Gaucher disease and the greatly improved safety profile of the transplant procedure, HSCT could be considered to provide permanent correction of systemic disease, including bone disease not ameliorated by ERT, when combined with emerging therapies directed at the neurological manifestations of disease; this could include ex-vivo gene therapy approaches.
    Keywords:  BMT; HSCT; Neurology; Neuronopathic Gaucher disease; Outcomes; Type 3 Gaucher disease
    DOI:  https://doi.org/10.1186/s13023-022-02378-7
  44. J Clin Med. 2022 Jun 13. pii: 3395. [Epub ahead of print]11(12):
    mTOR Inhibitor Treatment in Patients with Tuberous Sclerosis Complex Is Associated with Specific Changes in microRNA Serum Profile.
    Bartłomiej Pawlik, Urszula Smyczyńska, Szymon Grabia, Wojciech Fendler, Izabela Dróżdż, Katarzyna Bąbol-Pokora, Katarzyna Kotulska, Sergiusz Jóźwiak, Julita Borkowska, Wojciech Młynarski, Joanna Trelińska.
      The aim of this study was to determine the serum profiles of miRNAs in patients with tuberous sclerosis (TSC) upon sirolimus treatment and compare them with those previously treated with everolimus in a similarly designed experiment. Serum microRNA profiling was performed in ten TSC patients before sirolimus therapy and again after 3-6 months using qPCR panels (Exiqon). Of 752 tested miRNAs, 28 showed significant differences in expression between TSC patients before and after sirolimus treatment. Of these, 11 miRNAs were dysregulated in the same directions as in the sirolimus groupcompared with the previously described everolimus group, miR-142-3p, miR-29c-3p, miR-150-5p, miR-425-5p, miR-376a-3p, miR-376a-3p, miR-532-3p, and miR-136-5p were upregulated, while miR-15b-3p, miR-100-5p, and miR-185-5p were downregulated. The most significant changes of expression, with fold changes exceeding 1.25 for both treatments, were noted for miR-136-5p, miR-376a-3p, and miR-150-5p. The results of a pathway analysis of the possible target genes for these miRNAs indicated the involvement of the Ras and MAPK signaling pathway. Upregulation of miR-136, miR-376a-3p, and miR-150-5p was noted in TSC patients treated with mTOR inhibitors, indicating a role in the downregulation of the mTOR pathway. Further studies are needed to determine the relationship between upregulated microRNAs and treatment efficacy.
    Keywords:  mTOR inhibitor; microRNA; sirolimus; tuberous sclerosis
    DOI:  https://doi.org/10.3390/jcm11123395
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