bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2022–11–20
ten papers selected by
Rich Giadone, Harvard University
  1. IRE-1 endoribonuclease activity declines early in C. elegans adulthood and is not rescued by reduced reproduction.
  2. Age-associated proteostasis collapse.
  3. Chaperone-mediated autophagy regulates adipocyte differentiation.
  4. Endoplasmic reticulum stress and lipids in health and diseases.
  5. This is how an Alzheimer's gene ravages the brain.
  6. Age reprogramming: cell rejuvenation by partial reprogramming.
  7. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes.
  8. HSP90β chaperoning SMURF1-mediated LATS proteasomal degradation in the regulation of bone formation.
  9. An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation.
  10. Human-Induced Pluripotent Stem Cell (hiPSC)-Derived Neurons and Glia for the Elucidation of Pathogenic Mechanisms in Alzheimer's Disease.
  1. Front Aging. 2022 ;3 1044556
    IRE-1 endoribonuclease activity declines early in C. elegans adulthood and is not rescued by reduced reproduction.
    Evandro A De-Souza, Nadia Cummins, Rebecca C Taylor.
      The proteome of a cell helps to define its functional specialization. Most proteins must be translated and properly folded to ensure their biological function, but with aging, animals lose their ability to maintain a correctly folded proteome. This leads to the accumulation of protein aggregates, decreased stress resistance, and the onset of age-related disorders. The unfolded protein response of the endoplasmic reticulum (UPRER) is a central protein quality control mechanism, the function of which is known to decline with age. Here, we show that age-related UPRER decline in Caenorhabditis elegans occurs at the onset of the reproductive period and is caused by a failure in IRE-1 endoribonuclease activities, affecting both the splicing of xbp-1 mRNA and regulated Ire1 dependent decay (RIDD) activity. Animals with a defect in germline development, previously shown to rescue the transcriptional activity of other stress responses during aging, do not show restored UPRER activation with age. This underlines the mechanistic difference between age-associated loss of UPRER activation and that of other stress responses in this system, and uncouples reproductive status from the activity of somatic maintenance pathways. These observations may aid in the development of strategies that aim to overcome the proteostasis decline observed with aging.
    Keywords:  C. elegans; IRE1; UPR; aging; cell stress; proteostasis; stress response; unfolded protein response
    DOI:  https://doi.org/10.3389/fragi.2022.1044556
  2. Yi Chuan. 2022 Sep 20. 44(9): 733-744
    Age-associated proteostasis collapse.
    Jia-Li Li, Jin Li, Hu Wang.
      Healthy cells utilize a series of protein quality regulatory networks to maintain the integrity and functionality of their proteome, named as protein homeostasis (proteostasis). However, the phenomenon of proteostasis collapse, including the destruction of the balance between protein synthesis, folding and degradation, are common with aging. The main causes of age-associated proteostasis collapse are as follows: (1) the decline in transcriptional activation of stress response related pathways, (2) the reduction of proteasome and autophagy activity, and (3) ribosome pausing during translation. In addition, proteostasis is regulated mainly through chaperones, proteasomes, and autophagy systems of proteostasis network in aging. This paper mainly reviews the causes of age-associated proteostasis collapse and the pathways of proteostasis regulation, which may open the way to explore aging studies and solve aging problems.
    Keywords:  aging; proteostasis collapse; proteostasis network
    DOI:  https://doi.org/10.16288/j.yczz.22-126
  3. Sci Adv. 2022 Nov 18. 8(46): eabq2733
    Chaperone-mediated autophagy regulates adipocyte differentiation.
    Susmita Kaushik, Yves R Juste, Kristen Lindenau, Shuxian Dong, Adrián Macho-González, Olaya Santiago-Fernández, Mericka McCabe, Rajat Singh, Evripidis Gavathiotis, Ana Maria Cuervo.
      Adipogenesis is a tightly orchestrated multistep process wherein preadipocytes differentiate into adipocytes. The most studied aspect of adipogenesis is its transcriptional regulation through timely expression and silencing of a vast number of genes. However, whether turnover of key regulatory proteins per se controls adipogenesis remains largely understudied. Chaperone-mediated autophagy (CMA) is a selective form of lysosomal protein degradation that, in response to diverse cues, remodels the proteome for regulatory purposes. We report here the activation of CMA during adipocyte differentiation and show that CMA regulates adipogenesis at different steps through timely degradation of key regulatory signaling proteins and transcription factors that dictate proliferation, energetic adaptation, and signaling changes required for adipogenesis.
    DOI:  https://doi.org/10.1126/sciadv.abq2733
  4. Prog Lipid Res. 2022 Nov 13. pii: S0163-7827(22)00053-4. [Epub ahead of print]89 101198
    Endoplasmic reticulum stress and lipids in health and diseases.
    Cenk Celik, Stella Yue Ting Lee, Wei Sheng Yap, Guillaume Thibault.
      The endoplasmic reticulum (ER) is a complex and dynamic organelle that regulates many cellular pathways, including protein synthesis, protein quality control, and lipid synthesis. When one or multiple ER roles are dysregulated and saturated, the ER enters a stress state, which, in turn, activates the highly conserved unfolded protein response (UPR). By sensing the accumulation of unfolded proteins or lipid bilayer stress (LBS) at the ER, the UPR triggers pathways to restore ER homeostasis and eventually induces apoptosis if the stress remains unresolved. In recent years, it has emerged that the UPR works intimately with other cellular pathways to maintain lipid homeostasis at the ER, and so does at cellular levels. Lipid distribution, along with lipid anabolism and catabolism, are tightly regulated, in part, by the ER. Dysfunctional and overwhelmed lipid-related pathways, independently or in combination with ER stress, can have reciprocal effects on other cellular functions, contributing to the development of diseases. In this review, we summarize the current understanding of the UPR in response to proteotoxic stress and LBS and the breadth of the functions mitigated by the UPR in different tissues and in the context of diseases.
    Keywords:  Cancer; Diabetes; Endoplasmic reticulum stress; Fatty liver; Immune response; Lipid bilayer stress; Lipid homeostasis; Lipotoxicity; Metabolic diseases; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.plipres.2022.101198
  5. Nature. 2022 Nov 16.
    This is how an Alzheimer's gene ravages the brain.
    Elie Dolgin.
      
    Keywords:  Alzheimer's disease
    DOI:  https://doi.org/10.1038/d41586-022-03724-2
  6. Development. 2022 Nov 15. pii: dev200755. [Epub ahead of print]149(22):
    Age reprogramming: cell rejuvenation by partial reprogramming.
    Prim B Singh, Assem Zhakupova.
      'Age reprogramming' refers to the process by which the molecular and cellular pathways of a cell that are subject to age-related decline are rejuvenated without passage through an embryonic stage. This process differs from the rejuvenation observed in differentiated derivatives of induced pluripotent stem cells, which involves passage through an embryonic stage and loss of cellular identity. Accordingly, the study of age reprogramming can provide an understanding of how ageing can be reversed while retaining cellular identity and the specialised function(s) of a cell, which will be of benefit to regenerative medicine. Here, we highlight recent work that has provided a more nuanced understanding of age reprogramming and point to some open questions in the field that might be explored in the future.
    Keywords:  Age reprogramming; Cellular identity; Epigenetic rejuvenation; H3K9me3; OSKM; Partial reprogramming
    DOI:  https://doi.org/10.1242/dev.200755
  7. Nature. 2022 Nov 16.
    APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes.
    Joel W Blanchard, Leyla Anne Akay, Jose Davila-Velderrain, Djuna von Maydell, Hansruedi Mathys, Shawn M Davidson, Audrey Effenberger, Chih-Yu Chen, Kristal Maner-Smith, Ihab Hajjar, Eric A Ortlund, Michael Bula, Emre Agbas, Ayesha Ng, Xueqiao Jiang, Martin Kahn, Cristina Blanco-Duque, Nicolas Lavoie, Liwang Liu, Ricardo Reyes, Yuan-Ta Lin, Tak Ko, Lea R'Bibo, William T Ralvenius, David A Bennett, Hugh P Cam, Manolis Kellis, Li-Huei Tsai.
      APOE4 is the strongest genetic risk factor for Alzheimer's disease1-3. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer's disease4-8. Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE2-6, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes-myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer's disease.
    DOI:  https://doi.org/10.1038/s41586-022-05439-w
  8. Cell Signal. 2022 Nov 12. pii: S0898-6568(22)00285-6. [Epub ahead of print] 110523
    HSP90β chaperoning SMURF1-mediated LATS proteasomal degradation in the regulation of bone formation.
    Meiyu Qu, Ying Gong, Yuyang Jin, Ruibo Gao, Qiangqiang He, Yana Xu, Tingyu Shen, Liu Mei, Chengyun Xu, Musaddique Hussain, Muhammad Qasim Barkat, Ximei Wu.
      Heat shock protein 90 (HSP90) molecular chaperone is responsible for the stabilization and biological activity of a diverse set of client proteins. We have previously demonstrated that inhibition of HSP90 by 17-Demethoxy-17-allyaminogeldanmycin (17-AAG) not only reverses the glucocorticoid-induced bone loss but also enhances the basal level of bone mass in mice. Here, we investigate the potential mechanism underlying HSP90-associated osteoblast differentiation and bone formation. Knockdown of HSP90β but not HSP90α or inhibition of HSP90 by 17-AAG or NVP-BEP800 negates the protein levels of large tumor suppressor (LATS), the core kinases of Hippo signaling, resulting in the inactivation of LATS and activation of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), in the enhancement of osteoblastic differentiation. In contrast, genetic ablation of Lats1 in mesenchymal stem cells is sufficient to abolish the HSP90 inhibition-induced osteoblastic differentiation and bone formation. Mechanistically, HSP90β but not HSP90α chaperones and prevents the SMAD specific E3 ubiquitin protein ligase 1 (SMURF1)-mediated and ubiquitination-dependent LATS protein proteasomal degradation, whereas 17-AAG abolishes these effects of HSP90β. Thus, these results uncover the HSP90β chaperoning SMURF1-mediated LATS protein proteasomal degradation and the subsequent YAP/TAZ activation as a hitherto uncharacterized mechanism controlling osteoblastic differentiation and bone formation.
    Keywords:  17-AAG; HSP90β; LATS; Osteoblast; SMURF1
    DOI:  https://doi.org/10.1016/j.cellsig.2022.110523
  9. Nat Commun. 2022 Nov 18. 13(1): 7084
    An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation.
    Mireia Seuma, Ben Lehner, Benedetta Bolognesi.
      Multiplexed assays of variant effects (MAVEs) guide clinical variant interpretation and reveal disease mechanisms. To date, MAVEs have focussed on a single mutation type-amino acid (AA) substitutions-despite the diversity of coding variants that cause disease. Here we use Deep Indel Mutagenesis (DIM) to generate a comprehensive atlas of diverse variant effects for a disease protein, the amyloid beta (Aβ) peptide that aggregates in Alzheimer's disease (AD) and is mutated in familial AD (fAD). The atlas identifies known fAD mutations and reveals that many variants beyond substitutions accelerate Aβ aggregation and are likely to be pathogenic. Truncations, substitutions, insertions, single- and internal multi-AA deletions differ in their propensity to enhance or impair aggregation, but likely pathogenic variants from all classes are highly enriched in the polar N-terminal region of Aβ. This comparative atlas highlights the importance of including diverse mutation types in MAVEs and provides important mechanistic insights into amyloid nucleation.
    DOI:  https://doi.org/10.1038/s41467-022-34742-3
  10. Methods Mol Biol. 2023 ;2561 105-133
    Human-Induced Pluripotent Stem Cell (hiPSC)-Derived Neurons and Glia for the Elucidation of Pathogenic Mechanisms in Alzheimer's Disease.
    Jessica E Young, Lawrence S B Goldstein.
      Alzheimer's disease (AD) is a common neurodegenerative disorder and a mechanistically complex disease. For the last decade, human models of AD using induced pluripotent stem cells (iPSCs) have emerged as a powerful way to understand disease pathogenesis in relevant human cell types. In this review, we summarize the state of the field and how this technology can apply to studies of both familial and sporadic studies of AD. We discuss patient-derived iPSCs, genome editing, differentiation of neural cell types, and three-dimensional organoids, and speculate on the future of this type of work for increasing our understanding of, and improving therapeutic development for, this devastating disease.
    Keywords:  Alzheimer’s disease; Human-induced pluripotent stem cells; Informed consent; Neuronal differentiation; Organoids
    DOI:  https://doi.org/10.1007/978-1-0716-2655-9_6
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