bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2022–11–27
seventeen papers selected by
Rich Giadone, Harvard University
  1. Functional diversification of heat shock factors.
  2. Loss of MTCH-1 suppresses age-related proteostasis collapse through the inhibition of programmed cell death factors.
  3. Neuroprotective effects of linear ubiquitin E3 ligase against aging-induced DNA damage and amyloid β neurotoxicity in the brain of Drosophila melanogaster.
  4. Brain injury triggers cell-type-specific and time-dependent endoplasmic reticulum stress responses.
  5. Analysis of Proteasome-Associated Ubiquitin Ligase Activity.
  6. Protein aggregation and calcium dysregulation are hallmarks of familial Parkinson's disease in midbrain dopaminergic neurons.
  7. Natural Products Targeting Hsp90 for a Concurrent Strategy in Glioblastoma and Neurodegeneration.
  8. Coexpression Network Construction and Visualization from Transcriptomes Underlying ER Stress Responses.
  9. Potential application of heat shock proteins as therapeutic targets in Parkinson's disease.
  10. Macroautophagy in quiescent and senescent cells: a pathway to longevity?
  11. Protein Misfolding and Aggregation in the Brain: Common Pathogenetic Pathways in Neurodegenerative and Mental Disorders.
  12. Conformational dynamics of the Hsp70 chaperone throughout key steps of its ATPase cycle.
  13. Pluripotent stem cell strategies for rebuilding the human brain.
  14. Daily briefing: How an Alzheimer's gene ravages the brain.
  15. A proteome-wide map of chaperone-assisted protein refolding in a cytosol-like milieu.
  16. Sedentary behavior and the biological hallmarks of aging.
  17. Opposing effects of apoE2 and apoE4 on microglial activation and lipid metabolism in response to demyelination.
  1. Biol Futur. 2022 Nov 19.
    Functional diversification of heat shock factors.
    Dániel Kovács, Márton Kovács, Saqib Ahmed, János Barna.
      Heat shock transcription factors (HSFs) are widely known as master regulators of the heat shock response. In invertebrates, a single heat shock factor, HSF1, is responsible for the maintenance of protein homeostasis. In vertebrates, seven members of the HSF family have been identified, namely HSF1, HSF2, HSF3, HSF4, HSF5, HSFX, and HSFY, of which HSF1 and HSF2 are clearly associated with heat shock response, while HSF4 is involved in development. Other members of the family have not yet been studied as extensively. Besides their role in cellular proteostasis, HSFs influence a plethora of biological processes such as aging, development, cell proliferation, and cell differentiation, and they are implicated in several pathologies such as neurodegeneration and cancer. This is achieved by regulating the expression of a great variety of genes including chaperones. Here, we review our current knowledge on the function of HSF family members and important aspects that made possible the functional diversification of HSFs.
    Keywords:  Functional diversification; Heat shock factors; Heat shock proteins; Heat shock response; Molecular evolution
    DOI:  https://doi.org/10.1007/s42977-022-00138-z
  2. Cell Rep. 2022 Nov 22. pii: S2211-1247(22)01564-9. [Epub ahead of print]41(8): 111690
    Loss of MTCH-1 suppresses age-related proteostasis collapse through the inhibition of programmed cell death factors.
    Yahyah Aman, Annmary Paul Erinjeri, Nikolaos Tataridas-Pallas, Rhianna Williams, Rachel Wellman, Hannah Chapman, John Labbadia.
      The age-related loss of protein homeostasis (proteostasis) is at the heart of numerous neurodegenerative diseases. Therefore, finding ways to preserve proteome integrity in aged cells may be a powerful way to promote long-term health. Here, we show that reducing the activity of a highly conserved mitochondrial outer membrane protein, MTCH-1/MTCH2, suppresses age-related proteostasis collapse in Caenorhabditis elegans without disrupting development, growth, or reproduction. Loss of MTCH-1 does not influence proteostasis capacity in aged tissues through previously described pathways but instead operates by reducing CED-4 levels. This results in the sequestration of HSP-90 by inactive CED-3, which in turn leads to an increase in HSF-1 activity, transcriptional remodeling of the proteostasis network, and maintenance of proteostasis capacity with age. Together, our findings reveal a role for programmed cell death factors in determining proteome health and suggest that inhibiting MTCH-1 activity in adulthood may safeguard the aging proteome and suppress age-related diseases.
    Keywords:  CP: Cell biology; Caenorhabditis elegans; HSF-1; HSP90; MTCH-1; aging; mitochondria; molecular chaperones; programmed cell death; protein homeostasis
    DOI:  https://doi.org/10.1016/j.celrep.2022.111690
  3. Biochem Biophys Res Commun. 2022 Nov 14. pii: S0006-291X(22)01581-9. [Epub ahead of print]637 196-202
    Neuroprotective effects of linear ubiquitin E3 ligase against aging-induced DNA damage and amyloid β neurotoxicity in the brain of Drosophila melanogaster.
    Byoungyun Choi, Chaejin Lim, Hyungi Lee, Ji-Eun Lee, Jaebum Kim, ChiHye Chung, Kyoung Sang Cho.
      E3 ubiquitin ligase, HOIL1-interacting protein (HOIP), forms the linear ubiquitin chain assembly complex (LUBAC) with HOIL and SHANK-associated RH domain interactor and catalyzes linear ubiquitination, directly linking the N- and C-termini of ubiquitin. Recently, several studies have implicated linear ubiquitination in aging and Alzheimer disease (AD). However, little is currently known about the roles of HOIP in brain aging and AD pathology. Here, we investigated the role of linear ubiquitin E3 ligase (LUBEL), a Drosophila HOIP ortholog, in brain aging and amyloid β (Aβ) pathology in a Drosophila AD model. DNA double-strand breaks (DSBs) were increased in the aged brains of neuron-specific LUBEL-knockdown flies compared to the age-matched controls. Silencing of LUBEL in the neuron of AD model flies increased the neuronal apoptosis and neurodegeneration, whereas silencing in glial cells had no such effect. Aβ aggregation levels and DSBs were also increased in the LUBEL-silenced AD model fly brains, but autophagy and proteostasis were not affected by LUBEL silencing. Collectively, our results suggest that LUBEL protects neurons from aging-induced DNA damage and Aβ neurotoxicity.
    Keywords:  Aging; Alzheimer disease; DNA double-strand break; Drosophila; LUBEL
    DOI:  https://doi.org/10.1016/j.bbrc.2022.11.032
  4. Glia. 2022 Nov 22.
    Brain injury triggers cell-type-specific and time-dependent endoplasmic reticulum stress responses.
    Qiyan Fan, Mika Takarada-Iemata, Nahoko Okitani, Takashi Tamatani, Hiroshi Ishii, Tsuyoshi Hattori, Sumiko Kiryu-Seo, Hiroshi Kiyama, Osamu Hori.
      The unfolded protein response (UPR) is a signal transduction network that responds to endoplasmic reticulum (ER) stress by coordinating protein homeostasis to maintain cell viability. The UPR can also trigger cell death when adaptive responses fail to improve protein homeostasis. Despite accumulating evidence suggesting that the UPR plays a role in neurodegenerative diseases and brain insults, our understanding of how ER stress is induced under neuropathological conditions is limited. Here, we investigated the cell- and time-specific patterns of the ER stress response after brain injury using ER stress-activated indicator (ERAI) mice, which enable monitoring of the UPR in vivo via increased fluorescence of a spliced XBP-1 protein fused with the green fluorescent protein (GFP) variant Venus. Following cortical stab injury of ERAI mice, the GFP signal and number of GFP+ cells increased in the ipsilateral cortex throughout the observation period (6 h to 7 days post-injury), confirming the induction of the UPR. GFP signals were observed in injured neurons early (from 6 h) after brain injury. However, non-neuronal cells, mainly endothelial cells followed by astrocytes, accounted for the majority of GFP+ cells after brain injury. Similar results were obtained in a mouse model of focal cerebral ischemia. These findings suggest that activation of the UPR in both neuronal and non-neuronal cells, especially endothelial cells and astrocytes, may play an important role in and could be a potential therapeutic target for acute brain injuries.
    Keywords:  ER stress; ERAI; UPR; astrocytes; brain injury; cerebral ischemia; endothelial cells
    DOI:  https://doi.org/10.1002/glia.24303
  5. Methods Mol Biol. 2023 ;2581 57-67
    Analysis of Proteasome-Associated Ubiquitin Ligase Activity.
    Zhishuo Wang, Beatriz Orosa-Puente, Steven H Spoel.
      The ubiquitin-proteasome system (UPS) is the predominant protein degradation machinery in eukaryotic cells. It is highly conserved among eukaryotes and essential for their survival. Through regulated proteolysis the UPS plays a key role in a myriad of cellular functions, including developmental and stress signaling, cell differentiation, and cell death. Attachment of a ubiquitin chain to a substrate can trigger its recruitment to the proteasome for proteolysis. To efficiently degrade substrates, however, the proteasome employs HECT-type ubiquitin ligases that can further remodel ubiquitin chains of proteasome-captured substrates. It is thought that this remodeling process is necessary to maintain substrate affinity for the proteasome and to completely translocate the substrate into the 20S proteolytic barrel. Here, we describe a protocol for purifying proteasomes and their associated accessory proteins and provide a practical way to detect proteasome-associated E3 ligase activity. This assay is reliable and efficient for assessing the ability of proteasomes to form ubiquitin conjugates and is applicable to a wide range of eukaryotic species.
    Keywords:  HECT-type ligases; Posttranslational modifications; Proteasome; Proteasome-associated ubiquitin E3 ligases; Ubiquitin
    DOI:  https://doi.org/10.1007/978-1-0716-2784-6_5
  6. NPJ Parkinsons Dis. 2022 Nov 24. 8(1): 162
    Protein aggregation and calcium dysregulation are hallmarks of familial Parkinson's disease in midbrain dopaminergic neurons.
    Gurvir S Virdi, Minee L Choi, James R Evans, Zhi Yao, Dilan Athauda, Stephanie Strohbuecker, Raja S Nirujogi, Anna I Wernick, Noelia Pelegrina-Hidalgo, Craig Leighton, Rebecca S Saleeb, Olga Kopach, Haya Alrashidi, Daniela Melandri, Jimena Perez-Lloret, Plamena R Angelova, Sergiy Sylantyev, Simon Eaton, Simon Heales, Dmitri A Rusakov, Dario R Alessi, Tilo Kunath, Mathew H Horrocks, Andrey Y Abramov, Rickie Patani, Sonia Gandhi.
      Mutations in the SNCA gene cause autosomal dominant Parkinson's disease (PD), with loss of dopaminergic neurons in the substantia nigra, and aggregation of α-synuclein. The sequence of molecular events that proceed from an SNCA mutation during development, to end-stage pathology is unknown. Utilising human-induced pluripotent stem cells (hiPSCs), we resolved the temporal sequence of SNCA-induced pathophysiological events in order to discover early, and likely causative, events. Our small molecule-based protocol generates highly enriched midbrain dopaminergic (mDA) neurons: molecular identity was confirmed using single-cell RNA sequencing and proteomics, and functional identity was established through dopamine synthesis, and measures of electrophysiological activity. At the earliest stage of differentiation, prior to maturation to mDA neurons, we demonstrate the formation of small β-sheet-rich oligomeric aggregates, in SNCA-mutant cultures. Aggregation persists and progresses, ultimately resulting in the accumulation of phosphorylated α-synuclein aggregates. Impaired intracellular calcium signalling, increased basal calcium, and impairments in mitochondrial calcium handling occurred early at day 34-41 post differentiation. Once midbrain identity fully developed, at day 48-62 post differentiation, SNCA-mutant neurons exhibited mitochondrial dysfunction, oxidative stress, lysosomal swelling and increased autophagy. Ultimately these multiple cellular stresses lead to abnormal excitability, altered neuronal activity, and cell death. Our differentiation paradigm generates an efficient model for studying disease mechanisms in PD and highlights that protein misfolding to generate intraneuronal oligomers is one of the earliest critical events driving disease in human neurons, rather than a late-stage hallmark of the disease.
    DOI:  https://doi.org/10.1038/s41531-022-00423-7
  7. Metabolites. 2022 Nov 21. pii: 1153. [Epub ahead of print]12(11):
    Natural Products Targeting Hsp90 for a Concurrent Strategy in Glioblastoma and Neurodegeneration.
    Sarmistha Mitra, Raju Dash, Yeasmin Akter Munni, Nusrat Jahan Selsi, Nasrin Akter, Md Nazim Uddin, Kishor Mazumder, Il Soo Moon.
      Glioblastoma multiforme (GBM) is one of the most common aggressive, resistant, and invasive primary brain tumors that share neurodegenerative actions, resembling many neurodegenerative diseases. Although multiple conventional approaches, including chemoradiation, are more frequent in GBM therapy, these approaches are ineffective in extending the mean survival rate and are associated with various side effects, including neurodegeneration. This review proposes an alternative strategy for managing GBM and neurodegeneration by targeting heat shock protein 90 (Hsp90). Hsp90 is a well-known molecular chaperone that plays essential roles in maintaining and stabilizing protein folding to degradation in protein homeostasis and modulates signaling in cancer and neurodegeneration by regulating many client protein substrates. The therapeutic benefits of Hsp90 inhibition are well-known for several malignancies, and recent evidence highlights that Hsp90 inhibitors potentially inhibit the aggressiveness of GBM, increasing the sensitivity of conventional treatment and providing neuroprotection in various neurodegenerative diseases. Herein, the overview of Hsp90 modulation in GBM and neurodegeneration progress has been discussed with a summary of recent outcomes on Hsp90 inhibition in various GBM models and neurodegeneration. Particular emphasis is also given to natural Hsp90 inhibitors that have been evidenced to show dual protection in both GBM and neurodegeneration.
    Keywords:  Hsp90; chemosensitivity; glioblastoma; neurodegenerations
    DOI:  https://doi.org/10.3390/metabo12111153
  8. Methods Mol Biol. 2023 ;2581 385-401
    Coexpression Network Construction and Visualization from Transcriptomes Underlying ER Stress Responses.
    Dae Kwan Ko, Federica Brandizzi.
      Dynamic gene expression changes are primary cellular reactions in response to most stresses and developmental cues in all organisms, including plants. With the ever-decreasing cost and increasing access, high-throughput transcriptome analyses have become a significant research tool to understand a wide spectrum of complex gene regulatory mechanisms. However, it is still challenging to understand the complete picture of gene responses because of the interactive and dynamic nature of gene expression in biological networks. Coexpression network analyses followed by network mapping are being increasingly applied to overcome this challenge. In this chapter, we will introduce detailed instructions for performing a weighted coexpression network analysis (WGCNA) and network visualization using a transcriptome dataset obtained during recovery from endoplasmic reticulum (ER) stress in Arabidopsis thaliana. The streamlined workflow described here allows biologists to identify and visualize coexpression interactions among genes, accessing a comprehensive landscape of dynamic gene expression changes for further downstream analyses using their datasets.
    Keywords:  Coexpression network; Cytoscape; Gene regulation; The unfolded protein response; Transcription; WGCNA
    DOI:  https://doi.org/10.1007/978-1-0716-2784-6_27
  9. Neurochem Int. 2022 Nov 17. pii: S0197-0186(22)00178-4. [Epub ahead of print]162 105453
    Potential application of heat shock proteins as therapeutic targets in Parkinson's disease.
    Haodong Guo, Jingsong Yi, Fan Wang, Tong Lei, Hongwu Du.
      Parkinson's disease (PD) is a common chronic neurodegenerative disease, and the heat shock proteins (HSPs) are proved to be of great value for PD. In addition, HSPs can maintain protein homeostasis, degrade and inhibit protein aggregation by properly folding and activating intracellular proteins in PD. This study mainly summarizes the important roles of HSPs in PD and explores their feasibility as targets. We introduced the structural and functional characteristics of HSPs and the physiological functions of HSPs in PD. HSPs can protect neurons from damage by degrading aggregates with three mechanisms, including the aggregation and removing α-Synuclein (α-Syn) aggregates, promotion the autophagy of abnormal proteins, and inhibition the apoptosis of degenerated neurons. This study underscores the importance of HSPs as targets in PD and helps to expand new mechanisms in PD treatment strategies.
    Keywords:  Heat shock proteins; Oxidative stress; PROTAC; Parkinson's disease; α-Synuclein
    DOI:  https://doi.org/10.1016/j.neuint.2022.105453
  10. Trends Cell Biol. 2022 Nov 19. pii: S0962-8924(22)00235-5. [Epub ahead of print]
    Macroautophagy in quiescent and senescent cells: a pathway to longevity?
    Andrew Murley, Andrew Dillin.
      Cellular quiescence - reversible exit from the cell cycle - is an important feature of many cell types important for organismal health. Aging and cellular dysfunction compromise the survival and reactivation of quiescent cells over time. Studies suggest that autophagic processes and lysosomal function are critical to maintaining the function of quiescent cells, especially adult stem cells, throughout life. Findings also point to both pro-senescence and anti-senescence functions for macroautophagy depending on context. In this review, we will discuss these findings, unanswered questions on the role of macroautophagy and lysosomal function in quiescent and senescent cells, and the possibility for interventions that stimulate macroautophagy and lysosomes to promote quiescent cell function and tissue regeneration.
    Keywords:  aging; autophagy; lysosomes; quiescence; senescence
    DOI:  https://doi.org/10.1016/j.tcb.2022.10.004
  11. Int J Mol Sci. 2022 Nov 21. pii: 14498. [Epub ahead of print]23(22):
    Protein Misfolding and Aggregation in the Brain: Common Pathogenetic Pathways in Neurodegenerative and Mental Disorders.
    Aleksandra Ochneva, Yana Zorkina, Olga Abramova, Olga Pavlova, Valeriya Ushakova, Anna Morozova, Eugene Zubkov, Konstantin Pavlov, Olga Gurina, Vladimir Chekhonin.
      Mental disorders represent common brain diseases characterized by substantial impairments of social and cognitive functions. The neurobiological causes and mechanisms of psychopathologies still have not been definitively determined. Various forms of brain proteinopathies, which include a disruption of protein conformations and the formation of protein aggregates in brain tissues, may be a possible cause behind the development of psychiatric disorders. Proteinopathies are known to be the main cause of neurodegeneration, but much less attention is given to the role of protein impairments in psychiatric disorders' pathogenesis, such as depression and schizophrenia. For this reason, the aim of this review was to discuss the potential contribution of protein illnesses in the development of psychopathologies. The first part of the review describes the possible mechanisms of disruption to protein folding and aggregation in the cell: endoplasmic reticulum stress, dysfunction of chaperone proteins, altered mitochondrial function, and impaired autophagy processes. The second part of the review addresses the known proteins whose aggregation in brain tissue has been observed in psychiatric disorders (amyloid, tau protein, α-synuclein, DISC-1, disbindin-1, CRMP1, SNAP25, TRIOBP, NPAS3, GluA1, FABP, and ankyrin-G).
    Keywords:  DISC-1; NPAS3; autophagy; depression; endoplasmic reticulum; protein aggregation; protein misfolding; proteinopathy; schizophrenia; stress
    DOI:  https://doi.org/10.3390/ijms232214498
  12. Proc Natl Acad Sci U S A. 2022 Nov 29. 119(48): e2123238119
    Conformational dynamics of the Hsp70 chaperone throughout key steps of its ATPase cycle.
    Lukas Rohland, Roman Kityk, Luka Smalinskaitė, Matthias P Mayer.
      The 70 kDa heat shock proteins (Hsp70s) are highly versatile molecular chaperones that assist in a wide variety of protein-folding processes. They exert their functions by continuously cycling between states of low and high affinity for client polypeptides, driven by ATP-binding and hydrolysis. This cycling is tuned by cochaperones and clients. Although structures for the high and low client affinity conformations of Hsp70 and Hsp70 domains in complex with various cochaperones and peptide clients are available, it is unclear how structural rearrangements in the presence of cochaperones and clients are orchestrated in space and time. Here, we report insights into the conformational dynamics of the prokaryotic model Hsp70 DnaK throughout its adenosine-5'-triphosphate hydrolysis (ATPase) cycle using proximity-induced fluorescence quenching. Our data suggest that ATP and cochaperone-induced structural rearrangements in DnaK occur in a sequential manner and resolve hitherto unpredicted cochaperone and client-induced structural rearrangements. Peptides induce large conformational changes in DnaK·ATP prior to ATP hydrolysis, whereas a protein client induces significantly smaller changes but is much more effective in stimulating ATP hydrolysis. Analysis of the enthalpies of activation for the ATP-induced opening of the DnaK lid in the presence of clients indicates that the lid does not exert an enthalpic pulling force onto bound clients, suggesting entropic pulling as a major mechanism for client unfolding. Our data reveal important insights into the mechanics, allostery, and dynamics of Hsp70 chaperones. We established a methodology for understanding the link between dynamics and function, Hsp70 diversity, and activity modulation.
    Keywords:  allostery; conformational dynamics; molecular chaperones; power-stroke; protein folding
    DOI:  https://doi.org/10.1073/pnas.2123238119
  13. Front Aging Neurosci. 2022 ;14 1017299
    Pluripotent stem cell strategies for rebuilding the human brain.
    Francesco Limone, Joseph R Klim, Daniel A Mordes.
      Neurodegenerative disorders have been extremely challenging to treat with traditional drug-based approaches and curative therapies are lacking. Given continued progress in stem cell technologies, cell replacement strategies have emerged as concrete and potentially viable therapeutic options. In this review, we cover advances in methods used to differentiate human pluripotent stem cells into several highly specialized types of neurons, including cholinergic, dopaminergic, and motor neurons, and the potential clinical applications of stem cell-derived neurons for common neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, ataxia, and amyotrophic lateral sclerosis. Additionally, we summarize cellular differentiation techniques for generating glial cell populations, including oligodendrocytes and microglia, and their conceivable translational roles in supporting neural function. Clinical trials of specific cell replacement therapies in the nervous system are already underway, and several attractive avenues in regenerative medicine warrant further investigation.
    Keywords:  aging; brain regeneration; cell replacement therapies; developmental neuroscience; neurodegeneration; neurological diseases; pluripotent stem cells; regenerative medicine
    DOI:  https://doi.org/10.3389/fnagi.2022.1017299
  14. Nature. 2022 Nov 17.
    Daily briefing: How an Alzheimer's gene ravages the brain.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-022-03780-8
  15. Proc Natl Acad Sci U S A. 2022 Nov 29. 119(48): e2210536119
    A proteome-wide map of chaperone-assisted protein refolding in a cytosol-like milieu.
    Philip To, Yingzi Xia, Sea On Lee, Taylor Devlin, Karen G Fleming, Stephen D Fried.
      The journey by which proteins navigate their energy landscapes to their native structures is complex, involving (and sometimes requiring) many cellular factors and processes operating in partnership with a given polypeptide chain's intrinsic energy landscape. The cytosolic environment and its complement of chaperones play critical roles in granting many proteins safe passage to their native states; however, it is challenging to interrogate the folding process for large numbers of proteins in a complex background with most biophysical techniques. Hence, most chaperone-assisted protein refolding studies are conducted in defined buffers on single purified clients. Here, we develop a limited proteolysis-mass spectrometry approach paired with an isotope-labeling strategy to globally monitor the structures of refolding Escherichia coli proteins in the cytosolic medium and with the chaperones, GroEL/ES (Hsp60) and DnaK/DnaJ/GrpE (Hsp70/40). GroEL can refold the majority (85%) of the E. coli proteins for which we have data and is particularly important for restoring acidic proteins and proteins with high molecular weight, trends that come to light because our assay measures the structural outcome of the refolding process itself, rather than binding or aggregation. For the most part, DnaK and GroEL refold a similar set of proteins, supporting the view that despite their vastly different structures, these two chaperones unfold misfolded states, as one mechanism in common. Finally, we identify a cohort of proteins that are intransigent to being refolded with either chaperone. We suggest that these proteins may fold most efficiently cotranslationally, and then remain kinetically trapped in their native conformations.
    Keywords:  GroEL; chaperones; protein folding; proteomics; refoldability
    DOI:  https://doi.org/10.1073/pnas.2210536119
  16. Ageing Res Rev. 2022 Nov 21. pii: S1568-1637(22)00249-5. [Epub ahead of print] 101807
    Sedentary behavior and the biological hallmarks of aging.
    Jérémy Raffin, Philipe de Souto Barreto, Anne Pavy Le Traon, Bruno Vellas, Mylène Aubertin-Leheudre, Yves Rolland.
      While the benefits of physical exercise for a healthy aging are well-recognized, a growing body of evidence shows that sedentary behavior has deleterious health effects independently, to some extent, of physical activity levels. Yet, the increasing prevalence of sedentariness constitutes a major public health issue that contributes to premature aging but the potential cellular mechanisms through which prolonged immobilization may accelerate biological aging remain unestablished. This narrative review summarizes the impact of sedentary behavior using different models of extreme sedentary behaviors including bedrest, unilateral limb suspension and space travel studies, on the hallmarks of aging such as genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. We further highlight the remaining knowledge gaps that need more research in order to promote healthspan extension and to provide future contributions to the field of geroscience.
    Keywords:  Hallmarks of aging; bedrest; lower limb suspension; sedentary behavior; spaceflight
    DOI:  https://doi.org/10.1016/j.arr.2022.101807
  17. Mol Neurodegener. 2022 Nov 23. 17(1): 75
    Opposing effects of apoE2 and apoE4 on microglial activation and lipid metabolism in response to demyelination.
    Na Wang, Minghui Wang, Suren Jeevaratnam, Cassandra Rosenberg, Tadafumi C Ikezu, Francis Shue, Sydney V Doss, Alla Alnobani, Yuka A Martens, Melissa Wren, Yan W Asmann, Bin Zhang, Guojun Bu, Chia-Chen Liu.
       BACKGROUND: Abnormal lipid accumulation has been recognized as a key element of immune dysregulation in microglia whose dysfunction contributes to neurodegenerative diseases. Microglia play essential roles in the clearance of lipid-rich cellular debris upon myelin damage or demyelination, a common pathogenic event in neuronal disorders. Apolipoprotein E (apoE) plays a pivotal role in brain lipid homeostasis; however, the apoE isoform-dependent mechanisms regulating microglial response upon demyelination remain unclear.
    METHODS: To determine how apoE isoforms impact microglial response to myelin damage, 2-month-old apoE2-, apoE3-, and apoE4-targeted replacement (TR) mice were fed with normal diet (CTL) or 0.2% cuprizone (CPZ) diet for four weeks to induce demyelination in the brain. To examine the effects on subsequent remyelination, the cuprizone diet was switched back to regular chow for an additional two weeks. After treatment, brains were collected and subjected to immunohistochemical and biochemical analyses to assess the myelination status, microglial responses, and their capacity for myelin debris clearance. Bulk RNA sequencing was performed on the corpus callosum (CC) to address the molecular mechanisms underpinning apoE-mediated microglial activation upon demyelination.
    RESULTS: We demonstrate dramatic isoform-dependent differences in the activation and function of microglia upon cuprizone-induced demyelination. ApoE2 microglia were hyperactive and more efficient in clearing lipid-rich myelin debris, whereas apoE4 microglia displayed a less activated phenotype with reduced clearance efficiency, compared with apoE3 microglia. Transcriptomic profiling revealed that key molecules known to modulate microglial functions had differential expression patterns in an apoE isoform-dependent manner. Importantly, apoE4 microglia had excessive buildup of lipid droplets, consistent with an impairment in lipid metabolism, whereas apoE2 microglia displayed a superior ability to metabolize myelin enriched lipids. Further, apoE2-TR mice had a greater extent of remyelination; whereas remyelination was compromised in apoE4-TR mice.
    CONCLUSIONS: Our findings provide critical mechanistic insights into how apoE isoforms differentially regulate microglial function and the maintenance of myelin dynamics, which may inform novel therapeutic avenues for targeting microglial dysfunctions in neurodegenerative diseases.
    Keywords:  Demyelination; Lipid droplets; Microglia; Remyelination; apoE isoforms
    DOI:  https://doi.org/10.1186/s13024-022-00577-1
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