bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2022‒02‒27
27 papers selected by
Rich Giadone
Harvard University
  1. Stress-responsive regulation of extracellular proteostasis.
  2. How do protein aggregates escape quality control in neurodegeneration?
  3. Recent Advances in Our Molecular and Mechanistic Understanding of Misfolded Cellular Proteins in Alzheimer's Disease (AD) and Prion Disease (PrD).
  4. Crosstalk Between the NLRP3 Inflammasome/ASC Speck and Amyloid Protein Aggregates Drives Disease Progression in Alzheimer's and Parkinson's Disease.
  5. Quantitative Comparison of HSF1 Activators.
  6. Endogenous BiP reporter system for simultaneous identification of ER stress and antibody production in Chinese hamster ovary cells.
  7. Amyloidosis in Alzheimer's Disease: Pathogeny, Etiology, and Related Therapeutic Directions.
  8. Heat shock transcription factor HSF2 modulates the autophagy response through the BTG2-SOD2 axis.
  9. Stress-induced tyrosine phosphorylation of RtcB modulates IRE1 activity and signaling outputs.
  10. Targeting the Unfolded Protein Response as a Disease-Modifying Pathway in Dementia.
  11. ATase inhibition rescues age-associated proteotoxicity of the secretory pathway.
  12. Autophagy and skin wound healing.
  13. Proteasome inhibition-enhanced fracture repair is associated with increased mesenchymal progenitor cells in mice.
  14. An Essential Role for Alzheimer's-Linked Amyloid Beta Oligomers in Neurodevelopment: Transient Expression of Multiple Proteoforms during Retina Histogenesis.
  15. Lysine 63-linked ubiquitination of tau oligomers contributes to the pathogenesis of Alzheimer's disease.
  16. Treatments targeting autophagy ameliorate the age-related macular degeneration phenotype in mice lacking APOE (apolipoprotein E).
  17. A lipid viewpoint in the plant endoplasmic reticulum stress response.
  18. p53 SUMOylation Mediates AOPP-Induced Endothelial Senescence and Apoptosis Evasion.
  19. Caffeine and MDMA (Ecstasy) Exacerbate ER Stress Triggered by Hyperthermia.
  20. Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration.
  21. Mechanism of signal sequence handover from NAC to SRP on ribosomes during ER-protein targeting.
  22. Differential expression profiling of heat stressed tardigrades reveals major shift in the transcriptome.
  23. The protective role of HSP27 in ocular diseases.
  24. Aging and Clonal Behavior of Hematopoietic Stem Cells.
  25. Spreading of Aggregated α-Synuclein in Sagittal Organotypic Mouse Brain Slices.
  26. Targeting EDEM protects against ER stress and improves development and survival in C. elegans.
  27. Modeling Alzheimer's Disease in Caenorhabditis elegans.
  1. J Cell Biol. 2022 04 04. pii: e202112104. [Epub ahead of print]221(4):
    Stress-responsive regulation of extracellular proteostasis.
    Jaleh S Mesgarzadeh, Joel N Buxbaum, R Luke Wiseman.
      Genetic, environmental, and aging-related insults can promote the misfolding and subsequent aggregation of secreted proteins implicated in the pathogenesis of numerous diseases. This has led to considerable interest in understanding the molecular mechanisms responsible for regulating proteostasis in extracellular environments such as the blood and cerebrospinal fluid (CSF). Extracellular proteostasis is largely dictated by biological pathways comprising chaperones, folding enzymes, and degradation factors localized to the ER and extracellular space. These pathways limit the accumulation of nonnative, potentially aggregation-prone proteins in extracellular environments. Many reviews discuss the molecular mechanisms by which these pathways impact the conformational integrity of the secreted proteome. Here, we instead focus on describing the stress-responsive mechanisms responsible for adapting ER and extracellular proteostasis pathways to protect the secreted proteome from pathologic insults that challenge these environments. Further, we highlight new strategies to identify stress-responsive pathways involved in regulating extracellular proteostasis and describe the pathologic and therapeutic implications for these pathways in human disease.
    DOI:  https://doi.org/10.1083/jcb.202112104
  2. Trends Neurosci. 2022 Feb 21. pii: S0166-2236(22)00018-2. [Epub ahead of print]
    How do protein aggregates escape quality control in neurodegeneration?
    Margreet B Koopman, Luca Ferrari, Stefan G D Rüdiger.
      Protein aggregates are hallmarks of neurodegenerative diseases. The protein quality control (PQC) system normally prevents proteins from misfolding and accumulation; however, proteins somehow escape this control on disease. Here we review advances in the role of PQC in protein aggregation and neurodegeneration. We focus primarily on the protein Tau, which aggregates in Alzheimer's disease (AD) and other tauopathies. We also examine recent advances in amyloid fibril structures and the process of fibril formation via phase separation, which are shedding new light on the role of PQC in protein aggregation diseases. While specific components of the quality control system appear to be altered in disease, most chaperones and degradation factors are unchanged at the cellular end stage. Advancing the understanding of quality control factors in neurodegeneration, particularly in the early stages of disease, is among the key challenges for neurodegeneration research.
    Keywords:  Tau; amyloid fibrils; autophagy; liquid–liquid phase separation; neurodegeneration; protein quality control
    DOI:  https://doi.org/10.1016/j.tins.2022.01.006
  3. Biomolecules. 2022 Jan 20. pii: 166. [Epub ahead of print]12(2):
    Recent Advances in Our Molecular and Mechanistic Understanding of Misfolded Cellular Proteins in Alzheimer's Disease (AD) and Prion Disease (PrD).
    Walter J Lukiw.
      Naturally occurring neuron-abundant proteins including amyloid Aβ42 peptide and the microtubule-associated protein tau (MAPT) can, over time and under pathological situations, assume atypical conformations, altering their normal biological structure and function, and causing them to aggregate into insoluble and neurotoxic intracellular inclusions. These misfolded proteins ultimately contribute to the pathogenesis of several progressive, age-related and ultimately lethal human neurodegenerative disorders. The molecular mechanism of this pathological phenomenon of neuronal protein misfolding lends support to the 'prion hypothesis', which predicts that the aberrant folding of endogenous natural protein structures into unusual pathogenic isoforms can induce the atypical folding of other similar brain-abundant proteins, underscoring the age-related, progressive nature and potential transmissible and spreading capabilities of the aberrant protein isoforms that drive these invariably fatal neurological syndromes. The abnormal folding and aggregation of host proteins is a consistent feature of both amyloidopathies and tauopathies that encompass a continuous spectrum of brain diseases that include Alzheimer's disease (AD), prion disorders (PrD) such as scrapie in sheep and goats (Bovidae), experimental prion infection of rodents (Muridae), Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker syndrome (GSS) in humans (Hominidae), and other fatal prion-driven neurological disorders. Because AD patients accumulate both misfolded tau and Aβ peptides, AD may be somewhat unique as the first example of a 'double prion disorder'. This commentary will examine current research trends in this fascinating research area, with a special emphasis on AD and PrD, and the novel pathological misfolded protein processes common to both intractable neurological disorders.
    Keywords:  Alzheimer’s disease (AD); atypical protein folding; frontotemporal degeneration (FTD); prion disease (PrD); proteostasis; tauopathies
    DOI:  https://doi.org/10.3390/biom12020166
  4. Front Mol Neurosci. 2022 ;15 805169
    Crosstalk Between the NLRP3 Inflammasome/ASC Speck and Amyloid Protein Aggregates Drives Disease Progression in Alzheimer's and Parkinson's Disease.
    Jonathan Hulse, Kiran Bhaskar.
      Two key pathological hallmarks of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are the accumulation of misfolded protein aggregates and the chronic progressive neuroinflammation that they trigger. Numerous original research and reviews have provided a comprehensive understanding of how aggregated proteins (amyloid β, pathological tau, and α-synuclein) contribute to the disease, including driving sterile inflammation, in part, through the aggregation of multi-protein inflammasome complexes and the ASC speck [composed of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), Apoptosis-associated speck-like protein containing a C-terminal caspase activation and recruitment domain (ASC), and inflammatory caspase-1] involved in innate immunity. Here, we provide a unique perspective on the crosstalk between the aggregation-prone proteins involved in AD/PD and the multi-protein inflammasome complex/ASC speck that fuels feed-forward exacerbation of each other, driving neurodegeneration. Failed turnover of protein aggregates (both AD/PD related aggregates and the ASC speck) by protein degradation pathways, prionoid propagation of inflammation by the ASC speck, cross-seeding of protein aggregation by the ASC speck, and pro-aggregatory cleavage of proteins by caspase-1 are some of the mechanisms that exacerbate disease progression. We also review studies that provide this causal framework and highlight how the ASC speck serves as a platform for the propagation and spreading of inflammation and protein aggregation that drives AD and PD.
    Keywords:  ASC; Alzheimer’s disease; NLRP3; Parkinson’s disease; autophagy-lysosomal degradation; inflammasomes; neuroinflammation; protein aggregation
    DOI:  https://doi.org/10.3389/fnmol.2022.805169
  5. Mol Biotechnol. 2022 Feb 26.
    Quantitative Comparison of HSF1 Activators.
    Christoph Steurer, Sarah Kerschbaum, Christina Wegrostek, Stefan Gabriel, Ali Hallaj, Viktoria Ortner, Thomas Czerny, Elisabeth Riegel.
      The heat shock response (HSR) pathway is a highly conserved rescue mechanism, which protects the cells from harmful insults disturbing the cellular protein homeostasis via expression of chaperones. Furthermore, it was demonstrated to play crucial roles in various diseases like neurodegeneration and cancer. For neurodegenerative diseases, an overexpression of chaperones is a potential therapeutic approach to clear the cells from non-functional protein aggregates. Therefore, activators of the HSR pathway and its master regulator HSF1 are under close observation. There are numerous HSR activators published in the literature using different model systems, experimental designs, and readout assays. The aim of this work was to provide a quantitative comparison of a broad range of published activators using a newly developed HSF responsive dual-luciferase cell line. Contrary to natural target genes, which are regulated by multiple input pathways, the artificial reporter exclusively reacts to HSF activity. In addition, the results were compared to endogenous heat shock protein expression. As a result, great differences in the intensity of pathway activation were observed. In addition, a parallel viability assessment revealed high variability in the specificity of the drugs. Furthermore, the differences seen compared to published data indicate that some activators exhibit tissue-specific differences leading to interesting assumptions about the regulation of HSF1.
    Keywords:  HSF1; Heat shock response; Luciferase assay; Neurodegenerative disease
    DOI:  https://doi.org/10.1007/s12033-022-00467-3
  6. Metab Eng. 2022 Feb 17. pii: S1096-7176(22)00026-X. [Epub ahead of print]72 35-45
    Endogenous BiP reporter system for simultaneous identification of ER stress and antibody production in Chinese hamster ovary cells.
    Minji Kyeong, Jae Seong Lee.
      As the biopharmaceutical industry expands, improving the production of therapeutic proteins using Chinese hamster ovary (CHO) cells is important. However, excessive and complicated protein production causes protein misfolding and triggers endoplasmic reticulum (ER) stress. When ER stress occurs, cells mediate the unfolded protein response (UPR) pathway to restore protein homeostasis and folding capacity of the ER. However, when the cells fail to control prolonged ER stress, UPR induces apoptosis. Therefore, monitoring the degree of UPR is required to achieve high productivity and the desired quality. In this study, we developed a fluorescence-based UPR monitoring system for CHO cells. We integrated mGFP into endogenous HSPA5 encoding BiP, a major ER chaperone and the primary ER stress activation sensor, using CRISPR/Cas9-mediated targeted integration. The mGFP expression level changed according to the ER stress induced by chemical treatment and batch culture in the engineered cell line. Using this monitoring system, we demonstrated that host cells and recombinant CHO cell lines with different mean fluorescence intensities (MFI; basal expression levels of BiP) possess a distinct capacity for stress culture conditions induced by recombinant protein production. Antibody-producing recombinant CHO cell lines were generated using site-specific integration based on host cells equipped with the BiP reporter system. Targeted integrants showed a strong correlation between productivity and MFI, reflecting the potential of this monitoring system as a screening readout for high producers. Taken together, these data demonstrate the utility of the endogenous BiP reporter system for the detection of real-time dynamic changes in endogenous UPR and its potential for applications in recombinant protein production during CHO cell line development.
    Keywords:  BiP; Cell engineering; Chinese hamster ovary (CHO); ER stress; Recombinant protein production; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.ymben.2022.02.002
  7. Molecules. 2022 Feb 11. pii: 1210. [Epub ahead of print]27(4):
    Amyloidosis in Alzheimer's Disease: Pathogeny, Etiology, and Related Therapeutic Directions.
    Chen Ma, Fenfang Hong, Shulong Yang.
      The amyloid hypothesis of Alzheimer's disease has long been the predominant theory, suggesting that Alzheimer's disease is caused by the accumulation of amyloid beta protein (Aβ) in the brain, leading to neuronal toxicity in the central nervous system (CNS). Because of breakthroughs in molecular medicine, the amyloid pathway is thought to be central to the pathophysiology of Alzheimer's disease (AD). Currently, it is believed that altered biochemistry of the Aβ cycle remains a central biological feature of AD and is a promising target for treatment. This review provides an overview of the process of amyloid formation, explaining the transition from amyloid precursor protein to amyloid beta protein. Moreover, we also reveal the relationship between autophagy, cerebral blood flow, ACHE, expression of LRP1, and amyloidosis. In addition, we discuss the detailed pathogenesis of amyloidosis, including oxidative damage, tau protein, NFTs, and neuronal damage. Finally, we list some ways to treat AD in terms of decreasing the accumulation of Aβ in the brain.
    Keywords:  Alzheimer’s disease; amyloid beta protein; amyloid precursor protein; amyloidosis
    DOI:  https://doi.org/10.3390/molecules27041210
  8. Biochem Biophys Res Commun. 2022 Feb 12. pii: S0006-291X(22)00200-5. [Epub ahead of print]600 44-50
    Heat shock transcription factor HSF2 modulates the autophagy response through the BTG2-SOD2 axis.
    Abhijnya Kanugovi Vijayavittal, Pankaj Kumar, Sreedevi Sugunan, Chitra Joseph, Bharath Devaki, Khanderao Paithankar, Sreedhar Amere Subbarao.
      The heat shock transcription factor HSF1 regulates the inducible Hsp gene transcription, whereas HSF2 is involved in the constitutive transcription. HSFs can work for the non-heat shock genes transcription in a case-specific manner to facilitate normal cellular functions. Here, we demonstrate that HSF2 acts as an upstream regulator of heat shock-induced autophagy response in a rat histiocytoma. The heat-induced HSF2 transactivates the B-cell translocation gene-2 (BTG2) transcription, and the latter acts as a transcriptional coactivator for superoxide dismutase (SOD2). The altered HSF2 promoter occupancy on the BTG2 promoter enhances BTG2 transcription. Since SOD2 regulation is linked to mitochondrial redox sensing, HSF2 appears to act as a redox sensor in deciding the cell fate. The HSF2 shRNA or NFE2L2/BTG2 siRNA treatments have interfered with the autophagy response. We demonstrate that HSF2 is an upstream activator of autophagy response, and the HSF2-BTG2-SOD2 axis acts as a switch between the non-selective (micro/macro) and selective (chaperone-mediated) autophagy.
    Keywords:  Autophagy; BTG2; HSF2; Heat shock; NFE2L2; SOD2
    DOI:  https://doi.org/10.1016/j.bbrc.2022.02.018
  9. Life Sci Alliance. 2022 May;pii: e202201379. [Epub ahead of print]5(5):
    Stress-induced tyrosine phosphorylation of RtcB modulates IRE1 activity and signaling outputs.
    Alexandra Papaioannou, Federica Centonze, Alice Metais, Marion Maurel, Luc Negroni, Matías Gonzalez-Quiroz, Sayyed Jalil Mahdizadeh, Gabriella Svensson, Ensieh Zare, Alice Blondel, Albert C Koong, Claudio Hetz, Rémy Pedeux, Michel L Tremblay, Leif A Eriksson, Eric Chevet.
      ER stress is mediated by three sensors and the most evolutionary conserved IRE1α signals through its cytosolic kinase and endoribonuclease (RNase) activities. IRE1α RNase activity can either catalyze the initial step of XBP1 mRNA unconventional splicing or degrade a number of RNAs through regulated IRE1-dependent decay. Until now, the biochemical and biological outputs of IRE1α RNase activity have been well documented; however, the precise mechanisms controlling whether IRE1α signaling is adaptive or pro-death (terminal) remain unclear. We investigated those mechanisms and hypothesized that XBP1 mRNA splicing and regulated IRE1-dependent decay activity could be co-regulated by the IRE1α RNase regulatory network. We identified that RtcB, the tRNA ligase responsible for XBP1 mRNA splicing, is tyrosine-phosphorylated by c-Abl and dephosphorylated by PTP1B. Moreover, we show that the phosphorylation of RtcB at Y306 perturbs RtcB interaction with IRE1α, thereby attenuating XBP1 mRNA splicing. Our results demonstrate that the IRE1α RNase regulatory network is dynamically fine-tuned by tyrosine kinases and phosphatases upon various stresses and that the extent of RtcB tyrosine phosphorylation determines cell adaptive or death outputs.
    DOI:  https://doi.org/10.26508/lsa.202201379
  10. Int J Mol Sci. 2022 Feb 11. pii: 2021. [Epub ahead of print]23(4):
    Targeting the Unfolded Protein Response as a Disease-Modifying Pathway in Dementia.
    Emad Sidhom, John T O'Brien, Adrian J Butcher, Heather L Smith, Giovanna R Mallucci, Benjamin R Underwood.
      Dementia is a global medical and societal challenge; it has devastating personal, social and economic costs, which will increase rapidly as the world's population ages. Despite this, there are no disease-modifying treatments for dementia; current therapy modestly improves symptoms but does not change the outcome. Therefore, new treatments are urgently needed-particularly any that can slow down the disease's progression. Many of the neurodegenerative diseases that lead to dementia are characterised by common pathological responses to abnormal protein production and misfolding in brain cells, raising the possibility of the broad application of therapeutics that target these common processes. The unfolded protein response (UPR) is one such mechanism. The UPR is a highly conserved cellular stress response to abnormal protein folding and is widely dysregulated in neurodegenerative diseases. In this review, we describe the basic machinery of the UPR, as well as the evidence for its overactivation and pathogenicity in dementia, and for the marked neuroprotective effects of its therapeutic manipulation in murine models of these disorders. We discuss drugs identified as potential UPR-modifying therapeutic agents-in particular the licensed antidepressant trazodone-and we review epidemiological and trial data from their use in human populations. Finally, we explore future directions for investigating the potential benefit of using trazodone or similar UPR-modulating compounds for disease modification in patients with dementia.
    Keywords:  Alzheimer’s disease; dementia; integrated stress response; neurocognitive disorders; neurodegenerative disorders; neuroprotection; trazodone; unfolded protein response
    DOI:  https://doi.org/10.3390/ijms23042021
  11. Commun Biol. 2022 Feb 25. 5(1): 173
    ATase inhibition rescues age-associated proteotoxicity of the secretory pathway.
    Maeghan Murie, Yajing Peng, Michael J Rigby, Inca A Dieterich, Mark A Farrugia, Andreas Endresen, Anita Bhattacharyya, Luigi Puglielli.
      Malfunction of autophagy contributes to the progression of many chronic age-associated diseases. As such, improving normal proteostatic mechanisms is an active target for biomedical research and a key focal area for aging research. Endoplasmic reticulum (ER)-based acetylation has emerged as a mechanism that ensures proteostasis within the ER by regulating the induction of ER specific autophagy. ER acetylation is ensured by two ER-membrane bound acetyltransferases, ATase1 and ATase2. Here, we show that ATase inhibitors can rescue ongoing disease manifestations associated with the segmental progeria-like phenotype of AT-1 sTg mice. We also describe a pipeline to reliably identify ATase inhibitors with promising druggability properties. Finally, we show that successful ATase inhibitors can rescue the proteopathy of a mouse model of Alzheimer's disease. In conclusion, our study proposes that ATase-targeting approaches might offer a translational pathway for many age-associated proteopathies affecting the ER/secretory pathway.
    DOI:  https://doi.org/10.1038/s42003-022-03118-0
  12. Burns Trauma. 2022 ;10 tkac003
    Autophagy and skin wound healing.
    Haiyue Ren, Feng Zhao, Qiqi Zhang, Xing Huang, Zhe Wang.
      Autophagy is a lysosome-dependent, self-renewal mechanism that can degrade and recycle cellular components in eukaryotic cells to maintain the stability of the intracellular environment and the cells ability to cope with unfavorable environments. Numerous studies suggest that autophagy participates in regulating various cellular functions and is closely associated with the onset and progression of various diseases. Wound healing is a complex, multistep biological process that involves multiple cell types. Refractory wounds, which include diabetic skin ulcers, can seriously endanger human health. Previous studies have confirmed that autophagy plays an essential role in various phases of wound healing. Specifically, in the inflammatory phase, autophagy has an anti-infection effect and it negatively regulates the inflammatory response, which prevents excessive inflammation from causing tissue damage. In the proliferative phase, local hypoxia in the wound can induce autophagy, which plays a role in anti-apoptosis and anti-oxidative stress and promotes cell survival. Autophagy of vascular endothelial cells promotes wound angiogenesis and that of keratinocytes promotes their differentiation, proliferation and migration, which is conducive to the completion of wound re-epithelialisation. In the remodeling phase, autophagy of fibroblasts affects the formation of hypertrophic scars. Additionally, a refractory diabetic wound may be associated with increased levels of autophagy, and the regulation of mesenchymal stem cell autophagy may improve its application to wound healing. Therefore, understanding the relationship between autophagy and skin wound healing and exploring the molecular mechanism of autophagy regulation may provide novel strategies for the clinical treatment of wound healing.
    Keywords:  Autophagy; Diabetes; Mesenchymal stem cells; Skin; Wound healing; microRNA
    DOI:  https://doi.org/10.1093/burnst/tkac003
  13. PLoS One. 2022 ;17(2): e0263839
    Proteasome inhibition-enhanced fracture repair is associated with increased mesenchymal progenitor cells in mice.
    Hengwei Zhang, Xing Li, Jiatong Liu, Xi Lin, Lingpeng Pei, Brendan F Boyce, Lianping Xing.
      The ubiquitin/proteasome system controls the stability of Runx2 and JunB, proteins essential for differentiation of mesenchymal progenitor/stem cells (MPCs) to osteoblasts. Local administration of proteasome inhibitor enhances bone fracture healing by accelerating endochondral ossification. However, if a short-term administration of proteasome inhibitor enhances fracture repair and potential mechanisms involved have yet to be exploited. We hypothesize that injury activates the ubiquitin/proteasome system in callus, leading to elevated protein ubiquitination and degradation, decreased MPCs, and impaired fracture healing, which can be prevented by a short-term of proteasome inhibition. We used a tibial fracture model in Nestin-GFP reporter mice, in which a subgroup of MPCs are labeled by Nestin-GFP, to test our hypothesis. We found increased expression of ubiquitin E3 ligases and ubiquitinated proteins in callus tissues at the early phase of fracture repair. Proteasome inhibitor Bortezomib, given soon after fracture, enhanced fracture repair, which is accompanied by increased callus Nestin-GFP+ cells and their proliferation, and the expression of osteoblast-associated genes and Runx2 and JunB proteins. Thus, early treatment of fractures with Bortezomib could enhance the fracture repair by increasing the number and proliferation of MPCs.
    DOI:  https://doi.org/10.1371/journal.pone.0263839
  14. Int J Mol Sci. 2022 Feb 17. pii: 2208. [Epub ahead of print]23(4):
    An Essential Role for Alzheimer's-Linked Amyloid Beta Oligomers in Neurodevelopment: Transient Expression of Multiple Proteoforms during Retina Histogenesis.
    Samuel C Bartley, Madison T Proctor, Hongjie Xia, Evelyn Ho, Dong S Kang, Kristen Schuster, Maíra A Bicca, Henrique S Seckler, Kirsten L Viola, Steven M Patrie, Neil L Kelleher, Fernando G De Mello, William L Klein.
      Human amyloid beta peptide (Aβ) is a brain catabolite that at nanomolar concentrations can form neurotoxic oligomers (AβOs), which are known to accumulate in Alzheimer's disease. Because a predisposition to form neurotoxins seems surprising, we have investigated whether circumstances might exist where AβO accumulation may in fact be beneficial. Our investigation focused on the embryonic chick retina, which expresses the same Aβ as humans. Using conformation-selective antibodies, immunoblots, mass spectrometry, and fluorescence microscopy, we discovered that AβOs are indeed present in the developing retina, where multiple proteoforms are expressed in a highly regulated cell-specific manner. The expression of the AβO proteoforms was selectively associated with transiently expressed phosphorylated Tau (pTau) proteoforms that, like AβOs, are linked to Alzheimer's disease (AD). To test whether the AβOs were functional in development, embryos were cultured ex ovo and then injected intravitreally with either a beta-site APP-cleaving enzyme 1 (BACE-1) inhibitor or an AβO-selective antibody to prematurely lower the levels of AβOs. The consequence was disrupted histogenesis resulting in dysplasia resembling that seen in various retina pathologies. We suggest the hypothesis that embryonic AβOs are a new type of short-lived peptidergic hormone with a role in neural development. Such a role could help explain why a peptide that manifests deleterious gain-of-function activity when it oligomerizes in the aging brain has been evolutionarily conserved.
    Keywords:  avian embryo cultures; conformation-sensitive antibodies; neurodegeneration; neurodevelopment; tau
    DOI:  https://doi.org/10.3390/ijms23042208
  15. J Biol Chem. 2022 Feb 21. pii: S0021-9258(22)00206-X. [Epub ahead of print] 101766
    Lysine 63-linked ubiquitination of tau oligomers contributes to the pathogenesis of Alzheimer's disease.
    Nicha Puangmalai, Urmi Sengupta, Nemil Bhatt, Sagar Gaikwad, Mauro Montalbano, Arijit Bhuyan, Stephanie Garcia, Salome McAllen, Minal Sonawane, Cynthia Jerez, Yingxin Zhao, Rakez Kayed.
      Ubiquitin-modified tau aggregates are abundantly found in human brains diagnosed with Alzheimer's disease (AD) and other tauopathies. Soluble tau oligomers (TauO) are the most neurotoxic tau species that propagate pathology and elicit cognitive deficits, but whether ubiquitination contributes to tau formation and spreading is not fully understood. Here, we observe that K63-linked, but not K48- linked, ubiquitinated TauO accumulate at higher levels in AD brains compared to age-matched controls. Using mass spectrometry analyses, we identified 11 ubiquitinated sites on AD brain-derived TauO (AD TauO). We found that K63-linked TauO are associated with enhanced seeding activity and propagation in human tau-expressing primary neuronal and tau biosensor cells. Additionally, exposure of tau-inducible HEK cells to AD TauO with different ubiquitin linkages (wild type, K48, and K63) resulted in enhanced formation and secretion of K63-linked TauO, which was associated with impaired proteasome and lysosome functions. Multi-pathway analysis also revealed the involvement of K63-linked TauO in cell survival pathways, which are impaired in AD. Collectively, our study highlights the significance of selective TauO ubiquitination, which could influence tau aggregation, accumulation, and subsequent pathological propagation. The insights gained from this study hold great promise for targeted therapeutic intervention in AD and related tauopathies.
    Keywords:  Alzheimer’s disease; K63 ubiquitination; Tau pathology spreading; Tau secretion; proteasome impairment
    DOI:  https://doi.org/10.1016/j.jbc.2022.101766
  16. Autophagy. 2022 Feb 23. 1-17
    Treatments targeting autophagy ameliorate the age-related macular degeneration phenotype in mice lacking APOE (apolipoprotein E).
    Kirstan A Vessey, Andrew I Jobling, Mai X Tran, Anna Y Wang, Ursula Greferath, Erica L Fletcher.
      Age-related macular degeneration (AMD) is a leading cause of vision loss with recent evidence indicating an important role for macroautophagy/autophagy in disease progression. In this study we investigate the efficacy of targeting autophagy for slowing dysfunction in a mouse model with features of early AMD. Mice lacking APOE (apolipoprotein E; B6.129P2-Apoetm1UncJ/Arc) and C57BL/6 J- (wild-type, WT) mice were treated with metformin or trehalose in the drinking water from 5 months of age and the ocular phenotype investigated at 13 months. Control mice received normal drinking water. APOE-control mice had reduced retinal function and thickening of Bruch's membrane consistent with an early AMD phenotype. Immunohistochemical labeling showed reductions in MAP1LC3B/LC3 (microtubule-associated protein 1 light chain 3 beta) and LAMP1 (lysosomal-associated membrane protein 1) labeling in the photoreceptors and retinal pigment epithelium (RPE). This correlated with increased LC3-II:LC3-I ratio and alterations in protein expression in multiple autophagy pathways measured by reverse phase protein array, suggesting autophagy was slowed. Treatment of APOE-mice with metformin or trehalose ameliorated the loss of retinal function and reduced Bruch's membrane thickening, enhancing LC3 and LAMP1 labeling in the ocular tissues and restoring LC3-II:LC3-I ratio to WT levels. Protein analysis indicated that both treatments boost ATM-AMPK driven autophagy. Additionally, trehalose increased p-MAPK14/p38 to enhance autophagy. Our study shows that treatments targeting pathways to enhance autophagy have the potential for treating early AMD and provide support for the use of metformin, which has been found to reduce the risk of AMD development in human patients.Abbreviations:AMD: age-related macular degeneration; AMPK: 5' adenosine monophosphate-activated protein kinase APOE: apolipoprotein E; ATM: ataxia telangiectasia mutated; BCL2L1/Bcl-xL: BCL2-like 1; DAPI: 4'-6-diamidino-2-phenylindole; ERG: electroretinogram; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GCL: ganglion cell layer; INL: inner nuclear layer; IPL: inner plexiform layer; IS/OS: inner and outer photoreceptor segments; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; OCT: optical coherence tomography; ONL: outer nuclear layer; OPs: oscillatory potentials; p-EIF4EBP1: phosphorylated eukaryotic translation initiation factor 4E binding protein 1; p-MAPK14/p38: phosphorylated mitogen-activated protein kinase 14; RPE: retinal pigment epithelium; RPS6KB/p70 S6 kinase: ribosomal protein S6 kinase; SQSTM1/p62: sequestosome 1; TP53/TRP53/p53: tumor related protein 53; TSC2: TSC complex subunit 2; WT: wild type.
    Keywords:  B6.129P2-Apoetm1UncJ; bruch’s membrane; metformin; retina; retinal pigment epithelium; trehalose
    DOI:  https://doi.org/10.1080/15548627.2022.2034131
  17. J Exp Bot. 2022 Feb 23. pii: erac063. [Epub ahead of print]
    A lipid viewpoint in the plant endoplasmic reticulum stress response.
    Kazue Kanehara, Yueh Cho, Chao-Yuan Yu.
      Organisms including humans seem to be ever exposed to various changes, which often have undesirable effects, referred to as stress. Keeping up with the constant changes, eukaryotic cells may have evolved a number of relevant cellular processes, such as the endoplasmic reticulum (ER) stress response. Due to presumably intimate links between human diseases and the ER function, the ER stress response has been extensively investigated in the various organisms for a few decades. Now we are able to have a picture of the molecular mechanisms of the ER stress response, one of which, the unfolded protein response (UPR), is highly conserved among yeasts, mammals, higher plants, and green algae. In this review, we attempt to highlight the plant UPR from the perspective of lipids, especially membrane phospholipids. Phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn) are the most abundant membrane phospholipids in eukaryotic cells. The ratio of PtdCho to PtdEtn and unsaturation of fatty acyl tails in both phospholipids are critical factors for the UPR, but the biosynthetic pathway responsible for PtdCho and PtdEtn are distinct in animals and plants. We discuss the plant UPR in comparison with the system in yeasts and animals in the context of membrane phospholipids.
    Keywords:   Arabidopsis thaliana ; INOSITOL-REQUIRING ENZYME1 (IRE1); endoplasmic reticulum (ER) stress; fatty acid; inositol; lipid; membrane saturation; phospholipids; unfolded protein response (UPR)
    DOI:  https://doi.org/10.1093/jxb/erac063
  18. Front Cardiovasc Med. 2021 ;8 795747
    p53 SUMOylation Mediates AOPP-Induced Endothelial Senescence and Apoptosis Evasion.
    Yanjia Chen, Zhuanhua Liu, Hongyu Chen, Xingfu Huang, Xiaoxia Huang, Yang Lei, Qing Liang, Jiayi Wei, Qin Zhang, Xiaohua Guo, Qiaobing Huang.
      The aging of endothelial cells plays a critical role in the development of age-related vascular disease. We established a model of endothelial premature senescence by application of Advanced oxidation protein products (AOPPs) modified bovine serum albumin (AOPP-BSA) in human umbilical vein endothelial cells (HUVECs). This cellular senescence was accompanied with endothelial barrier dysfunction and angiogenesis impairment. It was further revealed that these senescent HUVECs underwent apoptosis evasion and the receptor for advanced glycation endproducts (RAGE) played a role in these processes. The AOPP-induced senescence was regulated by the state of autophagy in HUVECs. We further proved that AOPP-BSA attenuated the autophagy of HUVECs, led to p53 SUMOylation at K386, resulting in endothelial senescence. We also established the animal model of vascular senescence by using ApoE-/- mice fed with high-fat diet plus daily injection of AOPP-BSA to verify the role of p53 SUMOylation in vascular senescence. Combined with intraperitoneal injection of rapamycin, the effect of autophagy on AOPP-induced p53 SUMOylation was also confirmed in vivo. Our data indicates that p53 SUMOylation at K386 plays an important role in AOPP-induced endothelial senescence and apoptosis evasion, suggesting that p53 K386 SUMOylation may serve as a potential therapeutic target in protecting against vascular senescence.
    Keywords:  autophagy; endothelial senescence; evasion of apoptosis; p53 SUMOylation; vascular disease
    DOI:  https://doi.org/10.3389/fcvm.2021.795747
  19. Int J Mol Sci. 2022 Feb 10. pii: 1974. [Epub ahead of print]23(4):
    Caffeine and MDMA (Ecstasy) Exacerbate ER Stress Triggered by Hyperthermia.
    Kathleen A Trychta, Brandon K Harvey.
      Drugs of abuse can cause local and systemic hyperthermia, a known trigger of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Another trigger of ER stress and UPR is ER calcium depletion, which causes ER exodosis, the secretion of ER-resident proteins. In rodent models, club drugs such as 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') can create hyperthermic conditions in the brain and cause toxicity that is affected by the environmental temperature and the presence of other drugs, such as caffeine. In human studies, MDMA stimulated an acute, dose-dependent increase in core body temperature, but an examination of caffeine and MDMA in combination remains a topic for clinical research. Here we examine the secretion of ER-resident proteins and activation of the UPR under combined exposure to MDMA and caffeine in a cellular model of hyperthermia. We show that hyperthermia triggers the secretion of normally ER-resident proteins, and that this aberrant protein secretion is potentiated by the presence of MDMA, caffeine, or a combination of the two drugs. Hyperthermia activates the UPR but the addition of MDMA or caffeine does not alter the canonical UPR gene expression despite the drug effects on ER exodosis of UPR-related proteins. One exception was increased BiP/GRP78 mRNA levels in MDMA-treated cells exposed to hyperthermia. These findings suggest that club drug use under hyperthermic conditions exacerbates disruption of ER proteostasis, contributing to cellular toxicity.
    Keywords:  ER exodosis; KDEL receptor; MDMA; caffeine; hyperthermia
    DOI:  https://doi.org/10.3390/ijms23041974
  20. J Exp Med. 2022 Mar 07. pii: e20211275. [Epub ahead of print]219(3):
    Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration.
    Kazuhisa Ishida, Kaoru Yamada, Risa Nishiyama, Tadafumi Hashimoto, Itaru Nishida, Yoichiro Abe, Masato Yasui, Takeshi Iwatsubo.
      Accumulation of tau has been implicated in various neurodegenerative diseases termed tauopathies. Tau is a microtubule-associated protein but is also actively released into the extracellular fluids including brain interstitial fluid and cerebrospinal fluid (CSF). However, it remains elusive whether clearance of extracellular tau impacts tau-associated neurodegeneration. Here, we show that aquaporin-4 (AQP4), a major driver of the glymphatic clearance system, facilitates the elimination of extracellular tau from the brain to CSF and subsequently to deep cervical lymph nodes. Strikingly, deletion of AQP4 not only elevated tau in CSF but also markedly exacerbated phosphorylated tau deposition and the associated neurodegeneration in the brains of transgenic mice expressing P301S mutant tau. The current study identified the clearance pathway of extracellular tau in the central nervous system, suggesting that glymphatic clearance of extracellular tau is a novel regulatory mechanism whose impairment contributes to tau aggregation and neurodegeneration.
    DOI:  https://doi.org/10.1084/jem.20211275
  21. Science. 2022 Feb 25. 375(6583): 839-844
    Mechanism of signal sequence handover from NAC to SRP on ribosomes during ER-protein targeting.
    Ahmad Jomaa, Martin Gamerdinger, Hao-Hsuan Hsieh, Annalena Wallisch, Viswanathan Chandrasekaran, Zeynel Ulusoy, Alain Scaiola, Ramanujan S Hegde, Shu-Ou Shan, Nenad Ban, Elke Deuerling.
      The nascent polypeptide-associated complex (NAC) interacts with newly synthesized proteins at the ribosomal tunnel exit and competes with the signal recognition particle (SRP) to prevent mistargeting of cytosolic and mitochondrial polypeptides to the endoplasmic reticulum (ER). How NAC antagonizes SRP and how this is overcome by ER targeting signals are unknown. Here, we found that NAC uses two domains with opposing effects to control SRP access. The core globular domain prevented SRP from binding to signal-less ribosomes, whereas a flexibly attached domain transiently captured SRP to permit scanning of nascent chains. The emergence of an ER-targeting signal destabilized NAC's globular domain and facilitated SRP access to the nascent chain. These findings elucidate how NAC hands over the signal sequence to SRP and imparts specificity of protein localization.
    DOI:  https://doi.org/10.1126/science.abl6459
  22. Comp Biochem Physiol A Mol Integr Physiol. 2022 Feb 16. pii: S1095-6433(22)00027-7. [Epub ahead of print] 111169
    Differential expression profiling of heat stressed tardigrades reveals major shift in the transcriptome.
    Ricardo Cardoso Neves, Ask Møbjerg, Miyako Kodama, Jazmín Ramos-Madrigal, M Thomas P Gilbert, Nadja Møbjerg.
      Tardigrades are renowned for their extreme stress tolerance, which includes the ability to endure complete desiccation, high levels of radiation and very low sub-zero temperatures. Nevertheless, tardigrades appear to be vulnerable to high temperatures and thus the potential effects of global warming. Here, we provide the first analysis of transcriptome data obtained from heat stressed specimens of the eutardigrade Ramazzottius varieornatus, with the aim of providing new insights into the molecular processes affected by high temperatures. Specifically, we compare RNA-seq datasets obtained from active, heat-exposed (35 °C) tardigrades to that of active controls kept at 5 °C. Our data reveal a surprising shift in transcription, involving 9634 differentially expressed transcripts, corresponding to >35% of the transcriptome. The latter data are in striking contrast to the hitherto observed constitutive expression underlying tardigrade extreme stress tolerance and entrance into the latent state of life, known as cryptobiosis. Thus, when examining the molecular response, heat-stress appears to be more stressful for R. varieornatus than extreme conditions, such as desiccation or freezing. A gene ontology analysis reveals that the heat stress response involves a change in transcription and presumably translation, including an adjustment of metabolism, and, putatively, preparation for encystment and subsequent diapause. Among the differentially expressed transcripts we find heat-shock proteins as well as the eutardigrade specific proteins (CAHS, SAHS, MAHS, RvLEAM, and Dsup). The latter proteins thus seem to contribute to a general stress response, and may not be directly related to cryptobiosis.
    Keywords:  Cryptobiosis; Extreme environments; Global warming; Tardigrade; Transcriptomics
    DOI:  https://doi.org/10.1016/j.cbpa.2022.111169
  23. Mol Biol Rep. 2022 Feb 25.
    The protective role of HSP27 in ocular diseases.
    K Sooraj, Swati Shukla, Ranjeet Kaur, Jeewan Singh Titiyal, Jasbir Kaur.
      Heat shock proteins (HSPs) are stress-induced proteins that are important constituents of the cell's defense system. The activity of HSPs enhances when the cell undergoes undesirable environmental conditions like stress. The protective roles of HSPs are due to their molecular chaperone and anti-apoptotic functions. HSPs have a central role in the eye, and their malfunction has been associated with the manifestation of ocular diseases. Heat shock protein 27 (HSP27, HSPB1) is present in various ocular tissues, and it has been found to protect the eye from disease states such as retinoblastoma, uveal melanoma, glaucoma, and cataract. But some recent studies have shown the destructive role of HSP27 on retinal ganglionic cells. Thus, this article summarizes the role of heat shock protein 27 in eye and ocular diseases and will focus on the expression, regulation, and function of HSP27 in ocular complications.
    Keywords:  Apoptosis; HSPs; Heat shock protein 27; Molecular chaperone; Ocular diseases
    DOI:  https://doi.org/10.1007/s11033-022-07222-6
  24. Int J Mol Sci. 2022 Feb 09. pii: 1948. [Epub ahead of print]23(4):
    Aging and Clonal Behavior of Hematopoietic Stem Cells.
    Masayuki Yamashita, Atsushi Iwama.
      Hematopoietic stem cells (HSCs) are the only cell population that possesses both a self-renewing capacity and multipotency, and can give rise to all lineages of blood cells throughout an organism's life. However, the self-renewal capacity of HSCs is not infinite, and cumulative evidence suggests that HSCs alter their function and become less active during organismal aging, leading ultimately to the disruption of hematopoietic homeostasis, such as anemia, perturbed immunity and increased propensity to hematological malignancies. Thus, understanding how HSCs alter their function during aging is a matter of critical importance to prevent or overcome these age-related changes in the blood system. Recent advances in clonal analysis have revealed the functional heterogeneity of murine HSC pools that is established upon development and skewed toward the clonal expansion of functionally poised HSCs during aging. In humans, next-generation sequencing has revealed age-related clonal hematopoiesis that originates from HSC subsets with acquired somatic mutations, and has highlighted it as a significant risk factor for hematological malignancies and cardiovascular diseases. In this review, we summarize the current fate-mapping strategies that are used to track and visualize HSC clonal behavior during development or after stress. We then review the age-related changes in HSCs that can be inherited by daughter cells and act as a cellular memory to form functionally distinct clones. Altogether, we link aging of the hematopoietic system to HSC clonal evolution and discuss how HSC clones with myeloid skewing and low regenerative potential can be expanded during aging.
    Keywords:  aging; clonal hematopoiesis; fate mapping; hematopoietic stem cells
    DOI:  https://doi.org/10.3390/ijms23041948
  25. Biomolecules. 2022 Jan 19. pii: 163. [Epub ahead of print]12(2):
    Spreading of Aggregated α-Synuclein in Sagittal Organotypic Mouse Brain Slices.
    Buket Uçar, Nadia Stefanova, Christian Humpel.
      The accumulation of α-synuclein (α-syn) in the brain plays a role in synucleinopathies and it is hypothesized to spread in a prion-like fashion between connected brain regions. In the present study, we aim to investigate this spreading in well-characterized sagittal organotypic whole brain slices taken from postnatal wild type (WT) and transgenic mice overexpressing human α-syn under the promoter of proteolipid protein (PLP). Collagen hydrogels were loaded with monomers of human α-syn, as well as human and mouse pre-formed fibrils (PFFs), to allow local application and slow release. The spreading of α-syn was evaluated in different brain regions by immunohistochemistry for total α-syn and α-syn phosphorylated at the serine129 position (α-syn-P). The application of human and mouse PFFs of α-syn caused the aggregation and spreading of α-syn-P in the brain slices, which was pronounced the most at the region of hydrogel application and surrounding striatum, as well as along the median forebrain bundle. The organotypic slices from transgenic mice showed significantly more α-syn pathology than those from WT mice. The present study demonstrates that seeding with α-syn PFFs but not monomers induced intracellular α-syn pathology, which was significantly more prominent in brain slices with α-syn overexpression. This is consistent with the prion-like spreading theory of α-syn aggregates. The sagittal whole brain slices characterized in this study carry the potential to be used as a novel model to study α-syn pathology.
    Keywords:  PLP transgenic mice; organotypic brain slices; pre-formed fibrils; spreading; α-synuclein
    DOI:  https://doi.org/10.3390/biom12020163
  26. PLoS Genet. 2022 Feb 22. 18(2): e1010069
    Targeting EDEM protects against ER stress and improves development and survival in C. elegans.
    Simona Ghenea, Marioara Chiritoiu, Robi Tacutu, Antonio Miranda-Vizuete, Stefana Maria Petrescu.
      EDEM-1, EDEM-2 and EDEM-3 are key players for the quality control of newly synthesized proteins in the endoplasmic reticulum (ER) by accelerating disposal and degradation of misfolded proteins through ER Associated Degradation (ERAD). Although many previous studies reported the role of individual ERAD components especially in cell-based systems, still little is known about the consequences of ERAD dysfunction under physiological and ER stress conditions in the context of a multicellular organism. Here we report the first individual and combined characterization and functional interplay of EDEM proteins in Caenorhabditis elegans using single, double, and triple mutant combinations. We found that EDEM-2 has a major role in the clearance of misfolded proteins from ER under physiological conditions, whereas EDEM-1 and EDEM-3 roles become prominent under acute ER stress. In contrast to SEL-1 loss, the loss of EDEMs in an intact organism induces only a modest ER stress under physiological conditions. In addition, chronic impairment of EDEM functioning attenuated both XBP-1 activation and up-regulation of the stress chaperone GRP78/BiP, in response to acute ER stress. We also show that pre-conditioning to EDEM loss in acute ER stress restores ER homeostasis and promotes survival by activating ER hormesis. We propose a novel role for EDEM in fine-tuning the ER stress responsiveness that affects ER homeostasis and survival.
    DOI:  https://doi.org/10.1371/journal.pgen.1010069
  27. Biomedicines. 2022 Jan 26. pii: 288. [Epub ahead of print]10(2):
    Modeling Alzheimer's Disease in Caenorhabditis elegans.
    Javier Alvarez, Pilar Alvarez-Illera, Jaime Santo-Domingo, Rosalba I Fonteriz, Mayte Montero.
      Alzheimer's disease (AD) is the most frequent cause of dementia. After decades of research, we know the importance of the accumulation of protein aggregates such as β-amyloid peptide and phosphorylated tau. We also know that mutations in certain proteins generate early-onset Alzheimer's disease (EOAD), and many other genes modulate the disease in its sporadic form. However, the precise molecular mechanisms underlying AD pathology are still unclear. Because of ethical limitations, we need to use animal models to investigate these processes. The nematode Caenorhabditis elegans has received considerable attention in the last 25 years, since the first AD models overexpressing Aβ peptide were described. We review here the main results obtained using this model to study AD. We include works studying the basic molecular mechanisms of the disease, as well as those searching for new therapeutic targets. Although this model also has important limitations, the ability of this nematode to generate knock-out or overexpression models of any gene, single or combined, and to carry out toxicity, recovery or survival studies in short timeframes with many individuals and at low cost is difficult to overcome. We can predict that its use as a model for various diseases will certainly continue to increase.
    Keywords:  Alzheimer’s; C. elegans; amyloid precursor protein; new therapies; presenilin; tau protein; β-amyloid
    DOI:  https://doi.org/10.3390/biomedicines10020288
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