bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2023–01–29
sixteen papers selected by
Rich Giadone, Harvard University
  1. Defective proteostasis in Alzheimer's disease.
  2. Chaperone-mediated autophagy in neurodegenerative diseases: mechanisms and therapy.
  3. Small heat shock proteins operate as molecular chaperones in the mitochondrial intermembrane space.
  4. FUS ALS neurons activate major stress pathways and reduce translation as an early protective mechanism against neurodegeneration.
  5. A transient protein megacomplex that controls degradation of cell components.
  6. Endoplasmic reticulum associated degradation is essential for maintaining the viability or function of mature myelinating cells in adults.
  7. Age-related changes in tau and autophagy in human brain in the absence of neurodegeneration.
  8. ADP-ribose transferase PARP16 mediated-unfolded protein response contributes to neuronal cell damage in cerebral ischemia/reperfusion.
  9. Protein structure terminates doubt about how transcription stops.
  10. The role of altered protein acetylation in neurodegenerative disease.
  11. Visualization of translation and protein biogenesis at the ER membrane.
  12. Predicting progression to Alzheimer's disease with human hippocampal progenitors exposed to serum.
  13. The expression of anti-aging protein Klotho is increased during neural differentiation of bone marrow-derived mesenchymal stem cells.
  14. Liquid-liquid phase separation of amyloid-β oligomers modulates amyloid fibrils formation.
  15. Lamin A/C phosphorylation at serine 22 is a conserved heat shock response to regulate nuclear adaptation during stress.
  16. Towards a structurally resolved human protein interaction network.
  1. Ageing Res Rev. 2023 Jan 21. pii: S1568-1637(23)00021-1. [Epub ahead of print]85 101862
    Defective proteostasis in Alzheimer's disease.
    Danielle Cozachenco, Felipe C Ribeiro, Sergio T Ferreira.
      The homeostasis of cellular proteins, or proteostasis, is critical for neuronal function and for brain processes, including learning and memory. Increasing evidence indicates that defective proteostasis contributes to the progression of neurodegenerative disorders, including Alzheimer's disease (AD), the most prevalent form of dementia in the elderly. Proteostasis comprises a set of cellular mechanisms that control protein synthesis, folding, post-translational modification and degradation, all of which are deregulated in AD. Importantly, deregulation of proteostasis plays a key role in synapse dysfunction and in memory impairment, the major clinical manifestation of AD. Here, we discuss molecular pathways involved in protein synthesis and degradation that are altered in AD, and possible pharmacological approaches to correct these defects.
    Keywords:  Alzheimer’s disease; Amyloid-β oligomers; Autophagy; Degradation; ER stress; Protein synthesis; Proteostasis; Ubiquitin-proteasome system
    DOI:  https://doi.org/10.1016/j.arr.2023.101862
  2. Mol Cell Biochem. 2023 Jan 25.
    Chaperone-mediated autophagy in neurodegenerative diseases: mechanisms and therapy.
    Yi Liu, Lan Tan, Meng-Shan Tan.
      Chaperone-mediated autophagy (CMA) is the selective degradation process of intracellular components by lysosomes, which is required for the degradation of aggregate-prone proteins and contributes to proteostasis maintenance. Proteostasis is essential for normal cell function and survival, and it is determined by the balance of protein synthesis and degradation. Because postmitotic neurons are highly susceptible to proteostasis disruption, CMA is vital for the nervous system. Since Parkinson's disease (PD) was first linked to CMA dysfunction, an increasing number of studies have shown that CMA loss, as seen during aging, occurs in the pathogenetic process of neurodegenerative diseases. Here, we review the molecular mechanisms of CMA, as well as the physiological function and regulation of this autophagy pathway. Following, we highlight its potential role in neurodegenerative diseases, and the latest advances and challenges in targeting CMA in therapy of neurodegenerative diseases.
    Keywords:  Chaperone-mediated autophagy; LAMP2A; Mechanisms; Neurodegenerative diseases; Proteostasis; Therapy
    DOI:  https://doi.org/10.1007/s11010-022-04640-9
  3. Nat Cell Biol. 2023 Jan 23.
    Small heat shock proteins operate as molecular chaperones in the mitochondrial intermembrane space.
    Elias Adriaenssens, Bob Asselbergh, Pablo Rivera-Mejías, Sven Bervoets, Leen Vendredy, Vicky De Winter, Katrien Spaas, Riet de Rycke, Gert van Isterdael, Francis Impens, Thomas Langer, Vincent Timmerman.
      Mitochondria are complex organelles with different compartments, each harbouring their own protein quality control factors. While chaperones of the mitochondrial matrix are well characterized, it is poorly understood which chaperones protect the mitochondrial intermembrane space. Here we show that cytosolic small heat shock proteins are imported under basal conditions into the mitochondrial intermembrane space, where they operate as molecular chaperones. Protein misfolding in the mitochondrial intermembrane space leads to increased recruitment of small heat shock proteins. Depletion of small heat shock proteins leads to mitochondrial swelling and reduced respiration, while aggregation of aggregation-prone substrates is countered in their presence. Charcot-Marie-Tooth disease-causing mutations disturb the mitochondrial function of HSPB1, potentially linking previously observed mitochondrial dysfunction in Charcot-Marie-Tooth type 2F to its role in the mitochondrial intermembrane space. Our results reveal that small heat shock proteins form a chaperone system that operates in the mitochondrial intermembrane space.
    DOI:  https://doi.org/10.1038/s41556-022-01074-9
  4. Cell Rep. 2023 Jan 24. pii: S2211-1247(23)00036-0. [Epub ahead of print]42(2): 112025
    FUS ALS neurons activate major stress pathways and reduce translation as an early protective mechanism against neurodegeneration.
    Barbara Szewczyk, René Günther, Julia Japtok, Moritz J Frech, Marcel Naumann, Hyun O Lee, Andreas Hermann.
      Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder causing progressive loss of motor neurons. Mutations in Fused in sarcoma (FUS) leading to its cytoplasmic mislocalization cause a subset of ALS. Under stress, mutant FUS localizes to stress granules (SGs)-cytoplasmic condensates composed of RNA and various proteins. Aberrant dynamics of SGs is linked to the pathology of ALS. Here, using motor neurons (MNs) derived from human induced pluripotent stem cells, we show that, in mutant FUS, MN dynamics of SGs is disturbed. Additionally, heat-shock response (HSR) and integrated stress response (ISR) involved in the regulation of SGs are upregulated in mutant MNs. HSR activation correlates with the amount of cytoplasmic FUS mislocalization. While inhibition of SG formation, translation, or ISR does not influence survival of FUS ALS neurons, proteotoxicity that cannot be compensated with the activation of stress pathways is the main driver of neurodegeneration in early FUS ALS.
    Keywords:  CP: Neuroscience; FUS; amyotrophic lateral sclerosis; heat stress response; integrated stress response; neurodegeneration; protein translation; proteostasis; stress granules
    DOI:  https://doi.org/10.1016/j.celrep.2023.112025
  5. Nature. 2023 Jan 25.
    A transient protein megacomplex that controls degradation of cell components.
      
    Keywords:  Cell biology; Structural biology
    DOI:  https://doi.org/10.1038/d41586-022-04538-y
  6. Glia. 2023 Jan 28.
    Endoplasmic reticulum associated degradation is essential for maintaining the viability or function of mature myelinating cells in adults.
    Shuangchan Wu, Wensheng Lin.
      Endoplasmic reticulum associated degradation (ERAD) is responsible for recognition and degradation of unfolded or misfolded proteins in the ER. Sel1L is essential for the ERAD activity of Sel1L-Hrd1 complex, the best-known ERAD machinery. Using a continuous Sel1L knockout mouse model (CNP/Cre; Sel1LloxP/loxP mice), our previous studies showed that Sel1L knockout in myelinating cells, oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS), leads to adult-onset myelin abnormalities in the CNS and PNS. Because Sel1L is deleted in myelinating cells of CNP/Cre; Sel1LloxP/loxP mice starting at very early stage of differentiation, it is impossible to rule out the possibility that the adult-onset myelin abnormalities in these mice results from developmental myelination defects caused by Sel1L knockout in myelinating cells during development. Thus, using an inducible Sel1L knockout mouse model (PLP/CreERT ; Sel1LloxP/loxP mice) that has normal, intact myelin and myelinating cells in the adult CNS and PNS prior to tamoxifen treatment, we sought to determine if Sel1L knockout in mature myelinating cells of adult mice leads to myelin abnormalities in the CNS and PNS. We showed that Sel1L knockout in mature myelinating cells caused ERAD impairment, ER stress and UPR activation. Interesting, Sel1L knockout in mature oligodendrocytes impaired their myelinating function by suppressing myelin protein translation, and resulted in progressive myelin thinning in the adult CNS. Conversely, Sel1L knockout in mature Schwann cells led to Schwann cell apoptosis and demyelination in the adult PNS. These findings demonstrate the essential roles of ERAD in mature myelinating cells in the adult CNS and PNS under physiological conditions.
    Keywords:  ERAD; Schwann cell; Sel1L; UPR; myelin; oligodendrocyte
    DOI:  https://doi.org/10.1002/glia.24346
  7. PLoS One. 2023 ;18(1): e0262792
    Age-related changes in tau and autophagy in human brain in the absence of neurodegeneration.
    Shreyasi Chatterjee, Megan Sealey, Eva Ruiz, Chrysia M Pegasiou, Keeley Brookes, Sam Green, Anna Crisford, Michael Duque-Vasquez, Emma Luckett, Rebecca Robertson, Philippa Richardson, Girish Vajramani, Paul Grundy, Diederik Bulters, Christopher Proud, Mariana Vargas-Caballero, Amritpal Mudher.
      Tau becomes abnormally hyper-phosphorylated and aggregated in tauopathies like Alzheimers disease (AD). As age is the greatest risk factor for developing AD, it is important to understand how tau protein itself, and the pathways implicated in its turnover, change during aging. We investigated age-related changes in total and phosphorylated tau in brain samples from two cohorts of cognitively normal individuals spanning 19-74 years, without overt neurodegeneration. One cohort utilised resected tissue and the other used post-mortem tissue. Total soluble tau levels declined with age in both cohorts. Phosphorylated tau was undetectable in the post-mortem tissue but was clearly evident in the resected tissue and did not undergo significant age-related change. To ascertain if the decline in soluble tau was correlated with age-related changes in autophagy, three markers of autophagy were tested but only two appeared to increase with age and the third was unchanged. This implies that in individuals who do not develop neurodegeneration, there is an age-related reduction in soluble tau which could potentially be due to age-related changes in autophagy. Thus, to explore how an age-related increase in autophagy might influence tau-mediated dysfunctions in vivo, autophagy was enhanced in a Drosophila model and all age-related tau phenotypes were significantly ameliorated. These data shed light on age-related physiological changes in proteins implicated in AD and highlights the need to study pathways that may be responsible for these changes. It also demonstrates the therapeutic potential of interventions that upregulate turnover of aggregate-prone proteins during aging.
    DOI:  https://doi.org/10.1371/journal.pone.0262792
  8. FASEB J. 2023 Feb;37(2): e22788
    ADP-ribose transferase PARP16 mediated-unfolded protein response contributes to neuronal cell damage in cerebral ischemia/reperfusion.
    Jinghuan Wang, Jie Xu, Yejun Dong, Zhenghua Su, Haibi Su, Qianwen Cheng, Xinhua Liu.
      Ischemic stroke is known to cause the accumulation of misfolded proteins and loss of calcium homeostasis, leading to impairment of endoplasmic reticulum (ER) function and activating the unfolded protein response (UPR). PARP16 is an active (ADP-ribosyl)transferase known tail-anchored ER transmembrane protein with a cytosolic catalytic domain. Here, we find PARP16 is highly expressed in ischemic cerebral hemisphere and oxygen-glucose deprivation/reoxygenation (OGD/R)-treated immortalized hippocampal neuronal cell HT22. Using an adeno-associated virus-mediated PARP16 knockdown approach in mice, we find PARP16 knockdown decreases infarct demarcations and has a better neurological outcome after ischemic stroke. Our data indicate PARP16 knockdown decreases ER stress and neuronal death caused by OGD/R, whereas PARP16 overexpression promotes ER stress-mediated cell damage in primary cortical neurons. Furthermore, PARP16 functions mechanistically as ADP-ribosyltransferase to modulate the level of ADP-ribosylation of the corresponding PERK and IRE1α arm of the UPR, and such modifications mediate activation of PERK and IRE1α. Indeed, pharmacological stimulation of the UPR using Brefeldin A partly counteracts PARP16 knockdown-mediated neuronal protection upon OGD/R treatment. In conclusion, PARP16 plays a crucial role in post-ischemic UPR and PARP16 knockdown alleviates brain injury after ischemic stroke. This study demonstrates the potential of the PARP16-PERK/IRE1α axis as a target for neuronal survival in ischemic stroke.
    Keywords:  PARP16; endoplasmic reticulum; ischemia stroke; neuronal cell; oxygen-glucose deprivation/reoxygenation
    DOI:  https://doi.org/10.1096/fj.202201426RR
  9. Nature. 2023 Jan 25.
    Protein structure terminates doubt about how transcription stops.
    Fahad Rashid, James Berger.
      
    Keywords:  Molecular biology; Structural biology
    DOI:  https://doi.org/10.1038/d41586-023-00121-1
  10. Front Aging Neurosci. 2022 ;14 1025473
    The role of altered protein acetylation in neurodegenerative disease.
    Fariha Kabir, Rachel Atkinson, Anthony L Cook, Andrew James Phipps, Anna Elizabeth King.
      Acetylation is a key post-translational modification (PTM) involved in the regulation of both histone and non-histone proteins. It controls cellular processes such as DNA transcription, RNA modifications, proteostasis, aging, autophagy, regulation of cytoskeletal structures, and metabolism. Acetylation is essential to maintain neuronal plasticity and therefore essential for memory and learning. Homeostasis of acetylation is maintained through the activities of histone acetyltransferases (HAT) and histone deacetylase (HDAC) enzymes, with alterations to these tightly regulated processes reported in several neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Both hyperacetylation and hypoacetylation can impair neuronal physiological homeostasis and increase the accumulation of pathophysiological proteins such as tau, α-synuclein, and Huntingtin protein implicated in AD, PD, and HD, respectively. Additionally, dysregulation of acetylation is linked to impaired axonal transport, a key pathological mechanism in ALS. This review article will discuss the physiological roles of protein acetylation and examine the current literature that describes altered protein acetylation in neurodegenerative disorders.
    Keywords:  HATs; HDACs; PTMs; acetylation; cytoskeleton; neurodegenerative disease; proteostasis
    DOI:  https://doi.org/10.3389/fnagi.2022.1025473
  11. Nature. 2023 Jan 25.
    Visualization of translation and protein biogenesis at the ER membrane.
    Max Gemmer, Marten L Chaillet, Joyce van Loenhout, Rodrigo Cuevas Arenas, Dimitrios Vismpas, Mariska Gröllers-Mulderij, Fujiet A Koh, Pascal Albanese, Richard A Scheltema, Stuart C Howes, Abhay Kotecha, Juliette Fedry, Friedrich Förster.
      The dynamic ribosome-translocon complex, which resides at the endoplasmic reticulum (ER) membrane, produces a major fraction of the human proteome1,2. It governs the synthesis, translocation, membrane insertion, N-glycosylation, folding and disulfide-bond formation of nascent proteins. Although individual components of this machinery have been studied at high resolution in isolation3-7, insights into their interplay in the native membrane remain limited. Here we use cryo-electron tomography, extensive classification and molecular modelling to capture snapshots of mRNA translation and protein maturation at the ER membrane at molecular resolution. We identify a highly abundant classical pre-translocation intermediate with eukaryotic elongation factor 1a (eEF1a) in an extended conformation, suggesting that eEF1a may remain associated with the ribosome after GTP hydrolysis during proofreading. At the ER membrane, distinct polysomes bind to different ER translocons specialized in the synthesis of proteins with signal peptides or multipass transmembrane proteins with the translocon-associated protein complex (TRAP) present in both. The near-complete atomic model of the most abundant ER translocon variant comprising the protein-conducting channel SEC61, TRAP and the oligosaccharyltransferase complex A (OSTA) reveals specific interactions of TRAP with other translocon components. We observe stoichiometric and sub-stoichiometric cofactors associated with OSTA, which are likely to include protein isomerases. In sum, we visualize ER-bound polysomes with their coordinated downstream machinery.
    DOI:  https://doi.org/10.1038/s41586-022-05638-5
  12. Brain. 2023 Jan 27. pii: awac472. [Epub ahead of print]
    Predicting progression to Alzheimer's disease with human hippocampal progenitors exposed to serum.
    Aleksandra Maruszak, Edina Silajdžić, Hyunah Lee, Tytus Murphy, Benjamine Liu, Liu Shi, Chiara de Lucia, Abdel Douiri, Evgenia Salta, Alejo J Nevado, Charlotte E Teunissen, Pieter J Visser, Jack Price, Henrik Zetterberg, Simon Lovestone, Sandrine Thuret.
      Adult hippocampal neurogenesis is important for learning and memory and is altered early in Alzheimer's disease. As hippocampal neurogenesis is modulated by the circulatory systemic environment, evaluating a proxy of how hippocampal neurogenesis is affected by the systemic milieu could serve as an early biomarker for Alzheimer's disease progression. Here, we used an in vitro assay to model the impact of systemic environment on hippocampal neurogenesis. A human hippocampal progenitor cell line was treated with longitudinal serum samples from individuals with mild cognitive impairment, who either progressed to Alzheimer's disease or remained cognitively stable. Mild cognitive impairment to Alzheimer's disease progression was characterized most prominently with decreased proliferation, increased cell death and increased neurogenesis. A subset of 'baseline' cellular readouts together with education level were able to predict Alzheimer's disease progression. The assay could provide a powerful platform for early prognosis, monitoring disease progression and further mechanistic studies.
    Keywords:  Alzheimer’s disease; hippocampal progenitors; neurogenesis; prognostic biomarker
    DOI:  https://doi.org/10.1093/brain/awac472
  13. Cell Biochem Funct. 2023 Jan 27.
    The expression of anti-aging protein Klotho is increased during neural differentiation of bone marrow-derived mesenchymal stem cells.
    Bahareh Naeeni, Masoumeh Fakhr Taha, Mohamad Sajad Emami Aleagha, Abdolamir Allameh.
      Klotho, as an antiaging protein, is involved in the maintenance and differentiation of neuronal or glial cells and, therefore, has been noticed as a potential therapeutic target for neurodegenerative disorders. Expression of Klotho has been examined in different cells and organs, however, our information about the developmental pattern of this protein during differentiation of mesenchymal stem cells (MSCs) into neuron-like cells is limited. In this study, we conducted neural differentiation of mouse bone marrow-derived-MSCs and monitored the expression of Klotho together with selected neuron-specific genes at messenger RNA (mRNA) on days 7 and 14 of differentiation using quantitative real-time PCR. In addition, Klotho status at protein level was evaluated by immunocytochemistry. The results showed a significant change in the morphology of MSCs towards neuron-like cells. These changes were observed with progressive growth and formation of cell connections towards the formation of a chain of neuron-like cells which occurred in the second week of differentiation. Morphological changes were associated with a significant increase in the expression of neuron-specific genes like pax-6, neuN and, neurofilaments (NfL). Likewise, there was an increased expression of Klotho mRNA, and accumulation of Klotho protein in neuronal cell bodies, during the cellular differentiation of MSCs. These findings provided new evidence that neuronal differentiation from the MSCs is associated with increased expression of Klotho. These data may provide insight into the importance of Klotho protein in stem cell differentiation and regeneration in response to cell death in the central nervous system.
    Keywords:  Klotho; antiaging; differentiation; gene expression; mesenchymal stem cells; neuron-like cells
    DOI:  https://doi.org/10.1002/cbf.3777
  14. J Biol Chem. 2023 Jan 19. pii: S0021-9258(23)00058-3. [Epub ahead of print] 102926
    Liquid-liquid phase separation of amyloid-β oligomers modulates amyloid fibrils formation.
    Xinrui Gui, Shuang Feng, Zilong Li, Yanyan Li, Bernd Reif, Bingyang Shi, Zheng Niu.
      Soluble amyloid-β oligomers (AβOs) are proposed to instigate and mediate the pathology of Alzheimer's disease (AD), but the mechanisms involved are not clear. In this study, we reported that AβOs can undergo liquid-liquid phase separation (LLPS) to form liquid-like droplets in vitro. We determined that AβOs exhibited an α-helix conformation in a membrane-mimicking environment of sodium dodecyl sulfate (SDS). Importantly, SDS is capable of reconfiguring the assembly of different AβOs to induce their LLPS. Moreover, we found that droplet formation of AβOs was promoted by strong hydrated anions and weak hydrated cations, suggesting that hydrophobic interactions play a key role in mediating phase separation of AβOs. Finally, we observed that LLPS of AβOs can further promote Aβ to form amyloid fibrils, which can be modulated by (-)-epigallocatechin gallate (EGCG). Our study highlights amyloid oligomers as an important entity involved in protein liquid-to-solid phase transition and reveals the regulatory role of LLPS underlying amyloid protein aggregation, which may be relevant to the pathological process of AD.
    Keywords:  Alzheimer’s disease; amyloid-β oligomers; liquid-liquid phase separation; oligomerization; protein aggregation
    DOI:  https://doi.org/10.1016/j.jbc.2023.102926
  15. J Cell Sci. 2023 Jan 25. pii: jcs.259788. [Epub ahead of print]
    Lamin A/C phosphorylation at serine 22 is a conserved heat shock response to regulate nuclear adaptation during stress.
    Laura Virtanen, Emilia Holm, Mona Halme, Gun West, Fanny Lindholm, Josef Gullmets, Juho Irjala, Tiina Heliö, Artur Padzik, Annika Meinander, John E Eriksson, Pekka Taimen.
      The heat shock (HS) response is crucial for cell survival in harmful environments. Nuclear lamin A/C (LA/C), encoded by LMNA gene, contributes towards altered gene expression during HS, but the underlying mechanisms are poorly understood. Here we show that upon HS, LA/C is reversibly phosphorylated at Ser22 in concert with HSF1 activation in human cells, mouse cells and D. melanogaster in vivo. Consequently, the phosphorylation facilitated nucleoplasmic localization of LA/C and nuclear sphericity in response to HS. Interestingly, LA/C knock-out cells showed deformed nuclei after HS and were rescued by ectopic expression of wild-type LA, but not by a phosphomimetic (S22D) LA mutant. Furthermore, HS triggered concurrent downregulation of lamina-associated protein 2α (Lap2α) in wild-type LA/C expressing cells but a similar response was perturbed in LA/C knock-out cells and in LMNA mutant patient fibroblasts which showed impaired cell cycle arrest under HS and compromised survival at the recovery. Taken together, our results suggest that the altered phosphorylation stoichiometry of LA/C provides an evolutionary conserved mechanism to regulate lamina structure and serve nuclear adaptation and cell survival during HS.
    Keywords:  Heat shock; Heat shock response; Lamin A/C; Lap2α; Phosphorylation
    DOI:  https://doi.org/10.1242/jcs.259788
  16. Nat Struct Mol Biol. 2023 Jan 23.
    Towards a structurally resolved human protein interaction network.
    David F Burke, Patrick Bryant, Inigo Barrio-Hernandez, Danish Memon, Gabriele Pozzati, Aditi Shenoy, Wensi Zhu, Alistair S Dunham, Pascal Albanese, Andrew Keller, Richard A Scheltema, James E Bruce, Alexander Leitner, Petras Kundrotas, Pedro Beltrao, Arne Elofsson.
      Cellular functions are governed by molecular machines that assemble through protein-protein interactions. Their atomic details are critical to studying their molecular mechanisms. However, fewer than 5% of hundreds of thousands of human protein interactions have been structurally characterized. Here we test the potential and limitations of recent progress in deep-learning methods using AlphaFold2 to predict structures for 65,484 human protein interactions. We show that experiments can orthogonally confirm higher-confidence models. We identify 3,137 high-confidence models, of which 1,371 have no homology to a known structure. We identify interface residues harboring disease mutations, suggesting potential mechanisms for pathogenic variants. Groups of interface phosphorylation sites show patterns of co-regulation across conditions, suggestive of coordinated tuning of multiple protein interactions as signaling responses. Finally, we provide examples of how the predicted binary complexes can be used to build larger assemblies helping to expand our understanding of human cell biology.
    DOI:  https://doi.org/10.1038/s41594-022-00910-8
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