bims-lysosi 2021-09-12 papers

bims-lysosi

Biomed News

on Lysosomes and signaling

Issue of 2021–09–12
twenty papers selected by
Stephanie Fernandes, Max Planck Institute for Biology of Ageing

ORP1L mediated PI(4)P signaling at ER-lysosome-mitochondrion three-way contact contributes to mitochondrial division.
Lysosomal disorder boosts STING.
Molecular targets and approaches to restore autophagy and lysosomal capacity in neurodegenerative disorders.
LRRK2 along the Golgi and lysosome connection: a jamming situation.
Galectin Trafficking Pathway-Enabled Color-Switchable Detection of Lysosomal Membrane Permeabilization.
Rab7b regulates dendritic cell migration by linking lysosomes to the actomyosin cytoskeleton.
Nucleolipid Acid-Based Nanocarriers Restore Neuronal Lysosomal Acidification Defects.
Fission yeast TOR complex 1 phosphorylates Psk1 through evolutionarily conserved interaction mediated by the TOS motif.
Reconstruction of the Cytokine Signaling in Lysosomal Storage Diseases by Literature Mining and Network Analysis.
Diphthamide promotes TOR signaling by increasing the translation of proteins in the TORC1 pathway.
HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts.
Alleviation of a polyglucosan storage disorder by enhancement of autophagic glycogen catabolism.
They Might Cut It-Lysosomes and Autophagy in Mitotic Progression.
Rag GTPases suppress PRL-3 degradation and predict poor clinical diagnosis of cancer patients with low PRL-3 mRNA expression.
The Role and Regulatory Mechanism of Transcription Factor EB in Health and Diseases.
Increased mitochondrial calcium uptake and concomitant mitochondrial activity by presenilin loss promotes mTORC1 signaling to drive neurodegeneration.
Treatment of skeletal and non-skeletal alterations of Mucopolysaccharidosis type IVA by AAV-mediated gene therapy.
Phosphatidylinositol and phosphatidylinositol-3-phosphate activate HOPS to catalyze SNARE assembly, allowing small headgroup lipids to support the terminal steps of membrane fusion.
Renal and Extra Renal Manifestations in Adult Zebrafish Model of Cystinosis.
Cathepsin C inhibitors as anti-inflammatory drug discovery: Challenges and opportunities.

Nat Commun. 2021 Sep 09. 12(1): 5354

ORP1L mediated PI(4)P signaling at ER-lysosome-mitochondrion three-way contact contributes to mitochondrial division.

Maxime Boutry, Peter K Kim.

Mitochondrial division is not an autonomous event but involves multiple organelles, including the endoplasmic reticulum (ER) and lysosomes. Whereas the ER drives the constriction of mitochondrial membranes, the role of lysosomes in mitochondrial division is not known. Here, using super-resolution live-cell imaging, we investigate the recruitment of lysosomes to the site of mitochondrial division. We find that the ER recruits lysosomes to the site of division through the interaction of VAMP-associated proteins (VAPs) with the lysosomal lipid transfer protein ORP1L to induce a three-way contact between the ER, lysosome, and the mitochondrion. We also show that ORP1L might transport phosphatidylinositol-4-phosphate (PI(4)P) from lysosomes to mitochondria, as inhibiting its transfer or depleting PI(4)P at the mitochondrial division site impairs fission, demonstrating a direct role for PI(4)P in the division process. Our findings support a model where the ER recruits lysosomes to act in concert at the fission site for the efficient division of mitochondria.

DOI: https://doi.org/10.1038/s41467-021-25621-4
Nat Cell Biol. 2021 Sep 08.

Lysosomal disorder boosts STING.

Melina Casadio.

DOI: https://doi.org/10.1038/s41556-021-00753-3
Mol Aspects Med. 2021 Sep 03. pii: S0098-2997(21)00078-9. [Epub ahead of print] 101018

Molecular targets and approaches to restore autophagy and lysosomal capacity in neurodegenerative disorders.

Julie Bastien, Suchithra Menon, Mirko Messa, Beat Nyfeler.

Autophagy is a catabolic process that promotes cellular fitness by clearing aggregated protein species, pathogens and damaged organelles through lysosomal degradation. The autophagic process is particularly important in the nervous system where post-mitotic neurons rely heavily on protein and organelle quality control in order to maintain cellular health throughout the lifetime of the organism. Alterations of autophagy and lysosomal function are hallmarks of various neurodegenerative disorders. In this review, we conceptualize some of the mechanistic and genetic evidence pointing towards autophagy and lysosomal dysfunction as a causal driver of neurodegeneration. Furthermore, we discuss rate-limiting pathway nodes and potential approaches to restore pathway activity, from autophagy initiation, cargo sequestration to lysosomal capacity.

DOI: https://doi.org/10.1016/j.mam.2021.101018
Biochem Soc Trans. 2021 Sep 08. pii: BST20201146. [Epub ahead of print]

LRRK2 along the Golgi and lysosome connection: a jamming situation.

Giovanni Piccoli, Mattia Volta.

  Parkinson's disease (PD) is an age-related neurodegenerative disorder, clinically characterized by bradykinesia, rigidity, and resting tremor. Leucine-Rich Repeat Kinase 2 (LRRK2) is a large, multidomain protein containing two enzymatic domains. Missense mutations in its coding sequence are amongst the most common causes of familial PD. The physiological and pathological impact of LRRK2 is still obscure, but accumulating evidence supports a role for LRRK2 in membrane and vesicle trafficking, mainly functioning in the endosome-recycling system, (synaptic) vesicle trafficking, autophagy, and lysosome biology. LRRK2 binds and phosphorylates key regulators of the endomembrane systems and is dynamically localized at the Golgi. The impact of LRRK2 on the Golgi may reverberate throughout the entire endomembrane system and occur in multiple intersecting pathways, including endocytosis, autophagy, and lysosomal function. This would lead to overall dysregulation of cellular homeostasis and protein catabolism, leading to neuronal dysfunction and accumulation of toxic protein species, thus underlying the possible neurotoxic effect of LRRK2 mutations causing PD.

Keywords:  Golgi apparatus; LRRK2; lysosomes

DOI:  https://doi.org/10.1042/BST20201146
Anal Chem. 2021 Sep 07.

Galectin Trafficking Pathway-Enabled Color-Switchable Detection of Lysosomal Membrane Permeabilization.

Lei Gao, Shoufa Han.

Lysosomal membrane permeabilization (LMP) engaged in multiple human diseases is accompanied by relocation of cytosolic galectin into LMP+ lysosomes. We herein reported a galectin trafficking-targeted method to image LMP using two kinds of glyco-dendrimers, a sialic acid-terminated dendrimer labeled with pH-inert rhodamine and a lactose-terminated dendrimer labeled with fluorescein that becomes green-emissive in pH-elevated lysosomes. Albeit both accumulated in physiological lysosomes, the former is released from LMP+ lysosomes while the latter binds to galectin accumulated in LMP+ lysosomes and thus trapped in LMP+ lysosomes. Accordingly, LMP+ lysosomes exhibit loss of red fluorescence and turn-on green fluorescence due to loss of lysosomal acidity. This red-to-green color switch enables discernment of LMP+ lysosomes from physiological lysosomes and pH-elevated lysosomes and can be further utilized to detect LMP in distinct cell death pathways. These results suggest the utility of galectin trafficking pathway-integrated synthetic probes for detection of LMP, a key factor for diseased cells.

DOI: https://doi.org/10.1021/acs.analchem.1c02387
J Cell Sci. 2021 Sep 08. pii: jcs.259221. [Epub ahead of print]

Rab7b regulates dendritic cell migration by linking lysosomes to the actomyosin cytoskeleton.

Katharina Vestre, Irene Persiconi, Marita Borg Distefano, Nadia Mensali, Noemi Antonella Guadagno, Marine Bretou, Sébastien Wälchli, Catharina Arnold-Schrauf, Oddmund Bakke, Marc Dalod, Ana-Maria Lennon-Dumenil, Cinzia Progida.

  Lysosomal signaling facilitates the migration of immune cells by releasing calcium to activate the actin-based motor myosin II at the cell rear. However, how the actomyosin cytoskeleton physically associates to lysosomes is unknown. We have previously identified myosin II as a direct interactor of Rab7b, a small GTPase that mediates the transport from late endosomes/lysosomes to the TGN. Here, we show that Rab7b regulates the migration of dendritic cells (DCs) in 1- and 3-dimensional environments. DCs are immune sentinels that transport antigens from peripheral tissues to lymph nodes to activate T lymphocytes and initiate adaptive immune responses. We found that lack of Rab7b reduces myosin II light chain phosphorylation and the activation of the transcription factor EB (TFEB), which controls lysosomal signaling and is required for fast DC migration. Furthermore, we demonstrate that Rab7b interacts with the lysosomal calcium channel TRPML1, enabling the local activation of myosin II at the cell rear. Altogether, our findings identify Rab7b as the missing physical link between lysosomes and the actomyosin cytoskeleton, allowing control of immune cell migration through lysosomal signaling.

Keywords:  Actomyosin; Cell migration; Dendritic cells; Rab proteins; Rab7b

DOI:  https://doi.org/10.1242/jcs.259221
Front Chem. 2021 ;9 736554

Nucleolipid Acid-Based Nanocarriers Restore Neuronal Lysosomal Acidification Defects.

Mathias Brouillard, Philippe Barthélémy, Benjamin Dehay, Sylvie Crauste-Manciet, Valérie Desvergnes.

  Increasing evidence suggests that lysosomal dysfunction has a pathogenic role in neurodegenerative diseases. In particular, an increase in lysosomal pH has been reported in different cellular models of Parkinson's disease. Thus, targeting lysosomes has emerged as a promising approach. More specifically, regulating its pH could play a central role against the neurodegeneration process. To date, only a few agents specifically targeting lysosomal pH are reported in the literature, partly due to the challenge of crossing the Blood-Brain-Barrier (BBB), preventing drug penetration into the central nervous system (CNS). To develop chronic treatments for neurodegenerative diseases, crossing the BBB is crucial. We report herein the conception and synthesis of an innovative DNA derivative-based nanocarrier. Nucleolipids, carrying a biocompatible organic acid as an active ingredient, were designed and synthesized as prodrugs. They were successfully incorporated into an oil-in-water nanoemulsion vehicle to cross biological membranes and then release effectively biocompatible acidic components to restore the functional lysosomal pH of neuronal cells. Biological assays on a genetic cell model of Parkinson's disease highlighted the non-toxicity of such nucleolipids after cellular uptake and their ability (at c = 40 µM) to fully restore lysosomal acidity.

Keywords:  acidification; lysosome; nanocarrier; neurodegenerative disease; nucleolipid; oil-in-water nanoemulsion; pH

DOI:  https://doi.org/10.3389/fchem.2021.736554
J Cell Sci. 2021 Sep 09. pii: jcs.258865. [Epub ahead of print]

Fission yeast TOR complex 1 phosphorylates Psk1 through evolutionarily conserved interaction mediated by the TOS motif.

Yuichi Morozumi, Ai Hishinuma, Suguru Furusawa, Fajar Sofyantoro, Hisashi Tatebe, Kazuhiro Shiozaki.

  TOR complex 1 (TORC1) is a multi-subunit protein kinase complex that controls cellular growth in response to environmental cues. The regulatory subunits of mammalian TORC1 (mTORC1) include RAPTOR, which recruits mTORC1 substrates, such as S6K1 and 4EBP1, by interacting with their TOR signaling (TOS) motif. Despite the evolutionary conservation of TORC1, no TOS motif has been described in lower eukaryotes. Here, we show that the fission yeast S6 kinase Psk1 contains a TOS motif that interacts with Mip1, a RAPTOR ortholog. The TOS motif in Psk1 resembles those in mammals, including the conserved Phe and Asp residues essential for the Mip1 interaction and TORC1-dependent phosphorylation of Psk1. The binding of the TOS motif to Mip1 is dependent on Mip1 Tyr-533, whose equivalent in RAPTOR is known to interact with the TOS motif in their co-crystals. Furthermore, we utilized the mip1-Y533A mutation to screen the known TORC1 substrates in fission yeast and successfully identified Atg13 as a novel TOS motif-containing substrate. These results strongly suggest that the TOS motif represents an evolutionarily conserved mechanism of the substrate recognition by TORC1.

Keywords:  Fission yeast; Mip1; TOR complex 1 (TORC1); TOS motif

DOI:  https://doi.org/10.1242/jcs.258865
Front Cell Dev Biol. 2021 ;9 703489

Reconstruction of the Cytokine Signaling in Lysosomal Storage Diseases by Literature Mining and Network Analysis.

Silvia Parolo, Danilo Tomasoni, Pranami Bora, Alan Ramponi, Chanchala Kaddi, Karim Azer, Enrico Domenici, Susana Neves-Zaph, Rosario Lombardo.

  Lysosomal storage diseases (LSDs) are characterized by the abnormal accumulation of substrates in tissues due to the deficiency of lysosomal proteins. Among the numerous clinical manifestations, chronic inflammation has been consistently reported for several LSDs. However, the molecular mechanisms involved in the inflammatory response are still not completely understood. In this study, we performed text-mining and systems biology analyses to investigate the inflammatory signals in three LSDs characterized by sphingolipid accumulation: Gaucher disease, Acid Sphingomyelinase Deficiency (ASMD), and Fabry Disease. We first identified the cytokines linked to the LSDs, and then built on the extracted knowledge to investigate the inflammatory signals. We found numerous transcription factors that are putative regulators of cytokine expression in a cell-specific context, such as the signaling axes controlled by STAT2, JUN, and NR4A2 as candidate regulators of the monocyte Gaucher disease cytokine network. Overall, our results suggest the presence of a complex inflammatory signaling in LSDs involving many cellular and molecular players that could be further investigated as putative targets of anti-inflammatory therapies.

Keywords:  ASMD; Fabry; Gaucher; cytokine; lysosomal storage diseases; natural language processing; systems biology; text-mining

DOI:  https://doi.org/10.3389/fcell.2021.703489
Proc Natl Acad Sci U S A. 2021 Sep 14. pii: e2104577118. [Epub ahead of print]118(37):

Diphthamide promotes TOR signaling by increasing the translation of proteins in the TORC1 pathway.

Yugang Zhang, Zhewang Lin, Julia Zhu, Miao Wang, Hening Lin.

  Diphthamide, a modification found only on translation elongation factor 2 (EF2), was proposed to suppress -1 frameshifting in translation. Although diphthamide is conserved among all eukaryotes, exactly what proteins are affected by diphthamide deletion is not clear in cells. Through genome-wide profiling for a potential -1 frameshifting site, we identified that the target of rapamycin complex 1 (TORC1)/mammalian TORC1 (mTORC1) signaling pathway is affected by deletion of diphthamide. Diphthamide deficiency in yeast suppresses the translation of TORC1-activating proteins Vam6 and Rtc1. Interestingly, TORC1 signaling also promotes diphthamide biosynthesis, suggesting that diphthamide forms a positive feedback loop to promote translation under nutrient-rich conditions. Our results provide an explanation for why diphthamide is evolutionarily conserved and why diphthamide deletion can cause severe developmental defects.

Keywords:  TOR signaling; diphthamide; translation; −1 frameshifting

DOI:  https://doi.org/10.1073/pnas.2104577118
J Lipid Res. 2021 Sep 02. pii: S0022-2275(21)00096-1. [Epub ahead of print] 100114

HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts.

Nina H Pipalia, Syed Z Saad, Kanagaraj Subramanian, Abigail Cross, Aisha Al-Motawa, Kunal Garg, Brian S J Blagg, Len Neckers, Paul Helquist, Olaf Wiest, Daniel S Ory, Frederick R Maxfield.

  Niemann Pick type C1 (NPC1) disease is a lysosomal lipid storage disorder caused by mutations of the NPC1 gene. More than 300 disease-associated mutations are reported in patients, resulting in abnormal accumulation of unesterified cholesterol, glycosphingolipids and other lipids in late endosomes and lysosomes (LE/Ly) of many cell types. Previously, we showed that treatment of many different NPC1 mutant fibroblasts with histone deacetylase inhibitors resulted in reduction of cholesterol storage, and we found that this was associated with enhanced exit of the NPC1 protein from the endoplasmic reticulum and delivery to LE/Ly. This suggested that histone deacetylase inhibitors may work through changes in protein chaperones to enhance the folding of NPC1 mutants, allowing them to be delivered to LE/Ly. In this study we evaluated the effect of several HSP90 inhibitors on NPC1I1061T skin fibroblasts. We found that HSP90 inhibition resulted in clearance of cholesterol from LE/Ly, and this was associated with enhanced delivery of the mutant NPC1I1061T protein to LE/Ly. We also observed that inhibition of HSP90 increased the expression of HSP70, and overexpression of HSP70 also reduced cholesterol storage in NPC1I1061T fibroblasts. However, we did not see correction of cholesterol storage by arimoclomol, a drug that is reported to increase HSP70 expression, at doses up to 0.5 mM. These results indicate that manipulation of molecular chaperones may lead to effective treatments for NPC1 disease, but further investigation of mechanisms will be required.

Keywords:  Cholesterol; Drug therapy; Endocytosis; Fluorescence Microscopy; HSP70; HSP90; Lysosomal Storage; Niemann-Pick disease; arimoclomol; chaperone

DOI:  https://doi.org/10.1016/j.jlr.2021.100114
EMBO Mol Med. 2021 Sep 06. e14554

Alleviation of a polyglucosan storage disorder by enhancement of autophagic glycogen catabolism.

Or Kakhlon, Hilla Vaknin, Kumudesh Mishra, Jeevitha D'Souza, Monzer Marisat, Uri Sprecher, Shane Wald-Altman, Anna Dukhovny, Yuval Raviv, Benny Da'adoosh, Hamutal Engel, Sandrine Benhamron, Keren Nitzan, Sahar Sweetat, Anna Permyakova, Anat Mordechai, Hasan Orhan Akman, Hanna Rosenmann, Alexander Lossos, Joseph Tam, Berge A Minassian, Miguel Weil.

  This work employs adult polyglucosan body disease (APBD) models to explore the efficacy and mechanism of action of the polyglucosan-reducing compound 144DG11. APBD is a glycogen storage disorder (GSD) caused by glycogen branching enzyme (GBE) deficiency causing accumulation of poorly branched glycogen inclusions called polyglucosans. 144DG11 improved survival and motor parameters in a GBE knockin (Gbeys/ys ) APBD mouse model. 144DG11 reduced polyglucosan and glycogen in brain, liver, heart, and peripheral nerve. Indirect calorimetry experiments revealed that 144DG11 increases carbohydrate burn at the expense of fat burn, suggesting metabolic mobilization of pathogenic polyglucosan. At the cellular level, 144DG11 increased glycolytic, mitochondrial, and total ATP production. The molecular target of 144DG11 is the lysosomal membrane protein LAMP1, whose interaction with the compound, similar to LAMP1 knockdown, enhanced autolysosomal degradation of glycogen and lysosomal acidification. 144DG11 also enhanced mitochondrial activity and modulated lysosomal features as revealed by bioenergetic, image-based phenotyping and proteomics analyses. As an effective lysosomal targeting therapy in a GSD model, 144DG11 could be developed into a safe and efficacious glycogen and lysosomal storage disease therapy.

Keywords:  adult polyglucosan body disease; autophagy; glycogen; lysosomes; polyglucosan

DOI:  https://doi.org/10.15252/emmm.202114554
Front Cell Dev Biol. 2021 ;9 727538

They Might Cut It-Lysosomes and Autophagy in Mitotic Progression.

Saara Hämälistö, Jonathan Stahl-Meyer, Marja Jäättelä.

  The division of one cell into two looks so easy, as if it happens without any control at all. Mitosis, the hallmark of mammalian life is, however, tightly regulated from the early onset to the very last phase. Despite the tight control, errors in mitotic division occur frequently and they may result in various chromosomal instabilities and malignancies. The flow of events during mitotic progression where the chromosomes condensate and rearrange with the help of the cytoskeletal network has been described in great detail. Plasma membrane dynamics and endocytic vesicle movement upon deadhesion and reattachment of dividing cells are also demonstrated to be functionally important for the mitotic integrity. Other cytoplasmic organelles, such as autophagosomes and lysosomes, have until recently been considered merely as passive bystanders in this process. Accordingly, at the onset of nuclear envelope breakdown in prometaphase, the number of autophagic structures and lysosomes is reduced and the bulk autophagic machinery is suppressed for the duration of mitosis. This is believed to ensure that the exposed nuclear components are not unintentionally delivered to autophagic degradation. With the evolving technologies that allow the detection of subtle alterations in cytoplasmic organelles, our understanding of the small-scale regulation of intracellular organelles has deepened rapidly and we discuss here recent discoveries revealing unexpected roles for autophagy and lysosomes in the preservation of genomic integrity during mitosis.

Keywords:  autophagy; cathepsin B; chromosome segregation; lysosome; mitosis; spindle

DOI:  https://doi.org/10.3389/fcell.2021.727538
Biochem Biophys Res Commun. 2021 Aug 31. pii: S0006-291X(21)01272-9. [Epub ahead of print]576 108-116

Rag GTPases suppress PRL-3 degradation and predict poor clinical diagnosis of cancer patients with low PRL-3 mRNA expression.

Yin Shi, Shengfeng Xu, Natalie Y L Ngoi, Yuanjian Hui, Zu Ye.

  Ras-related GTP binding (Rag) GTPases are required to activate mechanistic target of rapamycin complex 1 (mTORC1), which plays a central role in cell growth and metabolism and is considered as one of the most important oncogenic pathways. Therefore, Rag GTPases have been speculated to play a pro-cancer role via mTOR induction. However, aside from stimulation of mTOR signaling, firm links connecting Rag GTPase activity and their downstream effectors with cancer progression, remain largely unreported. In this study, we reported a novel link between RagB/C and a known oncoprotein phosphatase of regenerating liver-3 (PRL-3) by screening 22 pairs of tumors and their adjacent normal tissues from gastric, liver and lung cancers, and validating our findings in cancer cell lines with ectopic RagB/C expression. RagB/C was found to enhance PRL-3 stability by modulating two major cellular protein degradation pathways: lysosomal-autophagy and ubiquitin-proteasome system (UPS). Functionally, we identified the correlation between RagB/C expression with poor clinical outcomes in breast or colon cancer patients who also showed low PRL-3 mRNA expression from data retrieved from TCGA datasets, highlighting the potential relevance of Rag GTPase and PRL-3 mRNA in combination as a prognostic clinical biomarker.

Keywords:  PRL-3; Protein stability; Rag GTPases

DOI:  https://doi.org/10.1016/j.bbrc.2021.08.090
Front Cell Dev Biol. 2021 ;9 667750

The Role and Regulatory Mechanism of Transcription Factor EB in Health and Diseases.

Sheng-Yu Zhu, Ren-Qi Yao, Yu-Xuan Li, Peng-Yue Zhao, Chao Ren, Xiao-Hui Du, Yong-Ming Yao.

  Transcription factor EB (TFEB) is a member of the microphthalmia-associated transcription factor/transcription factor E (MiTF/TFE) family and critically involved in the maintenance of structural integrity and functional balance of multiple cells. In this review, we described the effects of post-transcriptional modifications, including phosphorylation, acetylation, SUMOylation, and ubiquitination, on the subcellular localization and activation of TFEB. The activated TFEB enters into the nucleus and induces the expressions of targeted genes. We then presented the role of TFEB in the biosynthesis of multiple organelles, completion of lysosome-autophagy pathway, metabolism regulation, immune, and inflammatory responses. This review compiles existing knowledge in the understanding of TFEB regulation and function, covering its essential role in response to cellular stress. We further elaborated the involvement of TFEB dysregulation in the pathophysiological process of various diseases, such as the catabolic hyperactivity in tumors, the accumulation of abnormal aggregates in neurodegenerative diseases, and the aberrant host responses in inflammatory diseases. In this review, multiple drugs have also been introduced, which enable regulating the translocation and activation of TFEB, showing beneficial effects in mitigating various disease models. Therefore, TFEB might serve as a potential therapeutic target for human diseases. The limitation of this review is that the mechanism of TFEB-related human diseases mainly focuses on its association with lysosome and autophagy, which needs deep description of other mechanism in diseases progression after getting more advanced information.

Keywords:  autophagy; inflammation; organelles; transcription factor EB; tumor

DOI:  https://doi.org/10.3389/fcell.2021.667750
Aging Cell. 2021 Sep 09. e13472

Increased mitochondrial calcium uptake and concomitant mitochondrial activity by presenilin loss promotes mTORC1 signaling to drive neurodegeneration.

Kerry C Ryan, Zahra Ashkavand, Shaarika Sarasija, Jocelyn T Laboy, Rohan Samarakoon, Kenneth R Norman.

  Metabolic dysfunction and protein aggregation are common characteristics that occur in age-related neurodegenerative disease. However, the mechanisms underlying these abnormalities remain poorly understood. We have found that mutations in the gene encoding presenilin in Caenorhabditis elegans, sel-12, results in elevated mitochondrial activity that drives oxidative stress and neuronal dysfunction. Mutations in the human presenilin genes are the primary cause of familial Alzheimer's disease. Here, we demonstrate that loss of SEL-12/presenilin results in the hyperactivation of the mTORC1 pathway. This hyperactivation is caused by elevated mitochondrial calcium influx and, likely, the associated increase in mitochondrial activity. Reducing mTORC1 activity improves proteostasis defects and neurodegenerative phenotypes associated with loss of SEL-12 function. Consistent with high mTORC1 activity, we find that SEL-12 loss reduces autophagosome formation, and this reduction is prevented by limiting mitochondrial calcium uptake. Moreover, the improvements of proteostasis and neuronal defects in sel-12 mutants due to mTORC1 inhibition require the induction of autophagy. These results indicate that mTORC1 hyperactivation exacerbates the defects in proteostasis and neuronal function in sel-12 mutants and demonstrate a critical role of presenilin in promoting neuronal health.

Keywords:   Caenorhabditis elegans ; Alzheimer; aging; calcium; mTORC1; mitochondria; presenilin

DOI:  https://doi.org/10.1111/acel.13472
Nat Commun. 2021 Sep 09. 12(1): 5343

Treatment of skeletal and non-skeletal alterations of Mucopolysaccharidosis type IVA by AAV-mediated gene therapy.

Joan Bertolin, Víctor Sánchez, Albert Ribera, Maria Luisa Jaén, Miquel Garcia, Anna Pujol, Xavier Sánchez, Sergio Muñoz, Sara Marcó, Jennifer Pérez, Gemma Elias, Xavier León, Carles Roca, Veronica Jimenez, Pedro Otaegui, Francisca Mulero, Marc Navarro, Jesús Ruberte, Fatima Bosch.

Mucopolysaccharidosis type IVA (MPSIVA) or Morquio A disease, a lysosomal storage disorder, is caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency, resulting in keratan sulfate (KS) and chondroitin-6-sulfate accumulation. Patients develop severe skeletal dysplasia, early cartilage deterioration and life-threatening heart and tracheal complications. There is no cure and enzyme replacement therapy cannot correct skeletal abnormalities. Here, using CRISPR/Cas9 technology, we generate the first MPSIVA rat model recapitulating all skeletal and non-skeletal alterations experienced by patients. Treatment of MPSIVA rats with adeno-associated viral vector serotype 9 encoding Galns (AAV9-Galns) results in widespread transduction of bones, cartilage and peripheral tissues. This led to long-term (1 year) increase of GALNS activity and whole-body correction of KS levels, thus preventing body size reduction and severe alterations of bones, teeth, joints, trachea and heart. This study demonstrates the potential of AAV9-Galns gene therapy to correct the disabling MPSIVA pathology, providing strong rationale for future clinical translation to MPSIVA patients.

DOI: https://doi.org/10.1038/s41467-021-25697-y
Mol Biol Cell. 2021 Sep 08. mbcE21040191

Phosphatidylinositol and phosphatidylinositol-3-phosphate activate HOPS to catalyze SNARE assembly, allowing small headgroup lipids to support the terminal steps of membrane fusion.

Thomas Torng, William Wickner.

Intracellular membrane fusion requires Rab GTPases, tethers, SNAREs of the R, Qa, Qb, and Qc families, and SNARE chaperones of the Sec17 (SNAP), Sec18 (NSF), and SM (Sec1/Munc18) families. The vacuolar HOPS complex combines the functions of membrane tethering and SM catalysis of SNARE assembly. HOPS is activated for this catalysis by binding to the vacuolar lipids and Rab. Of the 8 major vacuolar lipids, we now report that phosphatidylinositol and phosphatidylinositol-3-phosphate are required to activate HOPS for SNARE complex assembly. These lipids plus ergosterol also allow full trans-SNARE complex assembly, yet do not support fusion, which is reliant on either phosphatidylethanolamine (PE) or on phosphatidic acid (PA), phosphatidylserine (PS), and diacylglycerol (DAG). Fusion with a synthetic tether and without HOPS, or even without SNAREs, still relies on either PE or on PS, PA, and DAG. These lipids are thus required for the terminal bilayer rearrangement step of fusion, distinct from the lipid requirements for the earlier step of activating HOPS for trans-SNARE assembly.

DOI: https://doi.org/10.1091/mbc.E21-07-0373
Int J Mol Sci. 2021 Aug 30. pii: 9398. [Epub ahead of print]22(17):

Renal and Extra Renal Manifestations in Adult Zebrafish Model of Cystinosis.

Sante Princiero Berlingerio, Junling He, Lies De Groef, Harold Taeter, Tomas Norton, Pieter Baatsen, Sara Cairoli, Bianca Goffredo, Peter de Witte, Lambertus van den Heuvel, Hans J Baelde, Elena Levtchenko.

  Cystinosis is a rare, incurable, autosomal recessive disease caused by mutations in the CTNS gene. This gene encodes the lysosomal cystine transporter cystinosin, leading to lysosomal cystine accumulation in all cells of the body, with kidneys being the first affected organs. The current treatment with cysteamine decreases cystine accumulation, but does not reverse the proximal tubular dysfunction, glomerular injury or loss of renal function. In our previous study, we have developed a zebrafish model of cystinosis through a nonsense mutation in the CTNS gene and have shown that zebrafish larvae recapitulate the kidney phenotype described in humans. In the current study, we characterized the adult cystinosis zebrafish model and evaluated the long-term effects of the disease on kidney and extra renal organs through biochemical, histological, fertility and locomotor activity studies. We found that the adult cystinosis zebrafish presents cystine accumulation in various organs, altered kidney morphology, impaired skin pigmentation, decreased fertility, altered locomotor activity and ocular anomalies. Overall, our data indicate that the adult cystinosis zebrafish model reproduces several human phenotypes of cystinosis and may be useful for studying pathophysiology and long-term effects of novel therapies.

Keywords:  adult phenotypic features; cystinosis; kidney disease; renal and extra renal manifestation; zebrafish model

DOI:  https://doi.org/10.3390/ijms22179398
Eur J Med Chem. 2021 Sep 03. pii: S0223-5234(21)00667-X. [Epub ahead of print]225 113818

Cathepsin C inhibitors as anti-inflammatory drug discovery: Challenges and opportunities.

Xiao Bao Shen, Xing Chen, Zhao Yan Zhang, Fu Fang Wu, Xin Hua Liu.

  Cathepsin C, an important lysosomal cysteine protease, mediates the maturation process of neutrophil serine proteases, and participates in the inflammation and immune regulation process associated with polymorphonuclear neutrophils. Therefore, cathepsin C is considered to be an attractive target for treating inflammatory diseases. With INS1007 (trade name: brensocatib) being granted a breakthrough drug designation by FDA for the treatment of Adult Non-cystic Fibrosis Bronchiectasis and Coronavirus Disease 2019, the development of cathepsin C inhibitor will attract attentions from medicinal chemists in the future soon. Here, we summarized the research results of cathepsin C as a therapeutic target, focusing on the development of cathepsin C inhibitor, and provided guidance and reference opinions for the upcoming development boom of cathepsin C inhibitor.

Keywords:  Cat C inhibitor; Cathepsin C; Inflammatory disease; Therapeutic target

DOI:  https://doi.org/10.1016/j.ejmech.2021.113818