bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2023‒05‒28
ten papers selected by
Rich Giadone
Harvard University
  1. Cellular Protein Aggregates: Formation, Biological Effects, and Ways of Elimination.
  2. Activation of endoplasmic reticulum stress in premature aging via the inner nuclear membrane protein SUN2.
  3. Chronic kidney disease promotes ageing in a multiorgan disease network.
  4. Myogenesis in C2C12 Cells Requires Phosphorylation of ATF6α by p38 MAPK.
  5. Coupled protein quality control during nonsense-mediated mRNA decay.
  6. Aerobic Exercise Delays Alzheimer's Disease by Regulating Mitochondrial Proteostasis in the Cerebral Cortex and Hippocampus.
  7. Dysfunctional Autophagy, Proteostasis, and Mitochondria as a Prelude to Age-Related Macular Degeneration.
  8. Heteromeric clusters of ubiquitinated ER-shaping proteins drive ER-phagy.
  9. Longitudinal changes in Alzheimer's-related plasma biomarkers and brain amyloid.
  10. Tau polarizes an aging transcriptional signature to excitatory neurons and glia.
  1. Int J Mol Sci. 2023 May 11. pii: 8593. [Epub ahead of print]24(10):
    Cellular Protein Aggregates: Formation, Biological Effects, and Ways of Elimination.
    Jun-Hao Wen, Xiang-Hong He, Ze-Sen Feng, Dong-Yi Li, Ji-Xin Tang, Hua-Feng Liu.
      The accumulation of protein aggregates is the hallmark of many neurodegenerative diseases. The dysregulation of protein homeostasis (or proteostasis) caused by acute proteotoxic stresses or chronic expression of mutant proteins can lead to protein aggregation. Protein aggregates can interfere with a variety of cellular biological processes and consume factors essential for maintaining proteostasis, leading to a further imbalance of proteostasis and further accumulation of protein aggregates, creating a vicious cycle that ultimately leads to aging and the progression of age-related neurodegenerative diseases. Over the long course of evolution, eukaryotic cells have evolved a variety of mechanisms to rescue or eliminate aggregated proteins. Here, we will briefly review the composition and causes of protein aggregation in mammalian cells, systematically summarize the role of protein aggregates in the organisms, and further highlight some of the clearance mechanisms of protein aggregates. Finally, we will discuss potential therapeutic strategies that target protein aggregates in the treatment of aging and age-related neurodegenerative diseases.
    Keywords:  age-related neurodegenerative diseases; aging; autophagy; protein aggregates; proteostasis; ubiquitin-proteasome system
    DOI:  https://doi.org/10.3390/ijms24108593
  2. Cell Rep. 2023 May 19. pii: S2211-1247(23)00545-4. [Epub ahead of print]42(5): 112534
    Activation of endoplasmic reticulum stress in premature aging via the inner nuclear membrane protein SUN2.
    Sandra Vidak, Leonid A Serebryannyy, Gianluca Pegoraro, Tom Misteli.
      One of the major cellular mechanisms to ensure cellular protein homeostasis is the endoplasmic reticulum (ER) stress response. This pathway is triggered by accumulation of misfolded proteins in the ER lumen. The ER stress response is also activated in the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). Here, we explore the mechanism of activation of the ER stress response in HGPS. We find that aggregation of the diseases-causing progerin protein at the nuclear envelope triggers ER stress. Induction of ER stress is dependent on the inner nuclear membrane protein SUN2 and its ability to cluster in the nuclear membrane. Our observations suggest that the presence of nucleoplasmic protein aggregates can be sensed, and signaled to the ER lumen, via clustering of SUN2. These results identify a mechanism of communication between the nucleus and the ER and provide insight into the molecular disease mechanisms of HGPS.
    Keywords:  CP: Cell biology; ER stress; Hutchinson-Gilford progeria syndrome; chaperones; transmembrane proteins; unfolded protein response
    DOI:  https://doi.org/10.1016/j.celrep.2023.112534
  3. Nat Rev Nephrol. 2023 May 26.
    Chronic kidney disease promotes ageing in a multiorgan disease network.
    Thomas Benzing, Björn Schumacher.
      
    DOI:  https://doi.org/10.1038/s41581-023-00729-6
  4. Biomedicines. 2023 May 16. pii: 1457. [Epub ahead of print]11(5):
    Myogenesis in C2C12 Cells Requires Phosphorylation of ATF6α by p38 MAPK.
    Valentina Pagliara, Giuseppina Amodio, Vincenzo Vestuto, Silvia Franceschelli, Nicola Antonino Russo, Vittorio Cirillo, Giovanna Mottola, Paolo Remondelli, Ornella Moltedo.
      Activating transcription factor 6α (ATF6α) is an endoplasmic reticulum protein known to participate in unfolded protein response (UPR) during ER stress in mammals. Herein, we show that in mouse C2C12 myoblasts induced to differentiate, ATF6α is the only pathway of the UPR activated. ATF6α stimulation is p38 MAPK-dependent, as revealed by the use of the inhibitor SB203580, which halts myotube formation and, at the same time, impairs trafficking of ATF6α, which accumulates at the cis-Golgi without being processed in the p50 transcriptional active form. To further evaluate the role of ATF6α, we knocked out the ATF6α gene, thus inhibiting the C2C12 myoblast from undergoing myogenesis, and this occurred independently from p38 MAPK activity. The expression of exogenous ATF6α in knocked-out ATF6α cells recover myogenesis, whereas the expression of an ATF6α mutant in the p38 MAPK phosphorylation site (T166) was not able to regain myogenesis. Genetic ablation of ATF6α also prevents the exit from the cell cycle, which is essential for muscle differentiation. Furthermore, when we inhibited differentiation by the use of dexamethasone in C2C12 cells, we found inactivation of p38 MAPK and, consequently, loss of ATF6α activity. All these findings suggest that the p-p38 MAPK/ATF6α axis, in pathophysiological conditions, regulates myogenesis by promoting the exit from the cell cycle, an essential step to start myoblasts differentiation.
    Keywords:  C2C12; activating transcription factor 6 α (ATF6α); myogenesis; p38 Mitogen-Activated Protein Kinase (MAPK); unfolded protein response
    DOI:  https://doi.org/10.3390/biomedicines11051457
  5. J Cell Sci. 2023 05 15. pii: jcs261216. [Epub ahead of print]136(10):
    Coupled protein quality control during nonsense-mediated mRNA decay.
    Alison J Inglis, Alina Guna, Ángel Gálvez-Merchán, Akshaye Pal, Theodore K Esantsi, Heather R Keys, Evgeni M Frenkel, Robert Oania, Jonathan S Weissman, Rebecca M Voorhees.
      Translation of mRNAs containing premature termination codons (PTCs) results in truncated protein products with deleterious effects. Nonsense-mediated decay (NMD) is a surveillance pathway responsible for detecting PTC containing transcripts. Although the molecular mechanisms governing mRNA degradation have been extensively studied, the fate of the nascent protein product remains largely uncharacterized. Here, we use a fluorescent reporter system in mammalian cells to reveal a selective degradation pathway specifically targeting the protein product of an NMD mRNA. We show that this process is post-translational and dependent on the ubiquitin proteasome system. To systematically uncover factors involved in NMD-linked protein quality control, we conducted genome-wide flow cytometry-based screens. Our screens recovered known NMD factors but suggested that protein degradation did not depend on the canonical ribosome-quality control (RQC) pathway. A subsequent arrayed screen demonstrated that protein and mRNA branches of NMD rely on a shared recognition event. Our results establish the existence of a targeted pathway for nascent protein degradation from PTC containing mRNAs, and provide a reference for the field to identify and characterize required factors.
    Keywords:  Nonsense-mediated decay; Quality control; Ubiquitin-proteasome pathway; mRNA
    DOI:  https://doi.org/10.1242/jcs.261216
  6. Life (Basel). 2023 May 17. pii: 1204. [Epub ahead of print]13(5):
    Aerobic Exercise Delays Alzheimer's Disease by Regulating Mitochondrial Proteostasis in the Cerebral Cortex and Hippocampus.
    Kaiyin Cui, Chaoyang Li, Guoliang Fang.
      In clinical practice, Alzheimer's disease (AD), as one of the main neurodegenerative diseases globally, currently has no cure. Recently, the delaying and improving effects of physical exercise on AD have gradually been confirmed; however, the specific mechanism involved needs further clarification. (1) Objective: Explore the mechanism aerobic exercise plays in delaying AD by regulating mitochondrial proteostasis and provide new theoretical bases for improving and delaying AD through aerobic exercise in the future. (2) Methods: Male APP/PS1 mice were randomly divided into a normal group (NG, n = 20), activation group (AG, n = 20), and inhibition group (SG, n = 20). Then, the mice in each group were randomly divided into control group and exercise group (n = 10 mice each), yielding the normal control group (CNG), normal exercise group (ENG), active control group (CAG), active exercise group (EAG), inhibitive control group (CSG), and inhibitive exercise group (ESG). After adaptive training, the mice in the exercise groups were trained on an aerobic treadmill for 12 weeks; we conducted behavioral tests and sampled the results. Then, quantitative real-time PCR (Q-PCR) and Western blot analysis were performed. (3) Results: In the Morris water maze (MWM) test, the latency was significantly reduced and the number of platform crossings was significantly increased in the CAG and ENG compared with the CNG, while the result of the CSG was contrary to this. Compared with the ENG, latency was significantly reduced and the number of platform crossings was significantly increased in the EAG, while the opposite occurred for ESG. Compared with the CAG, the latency was significantly reduced and the number of platform crossings was significantly increased in the EAG, while the results for CSG were contrary. In the step-down test, compared with the CNG, the latency was significantly increased and the number of errors was significantly reduced in the CAG and ENG, respectively, while the results for CSG were contrary. Compared with the ENG, the latency was significantly increased and the number of errors was significantly reduced in the EAG, while the results for ESG were contrary. Compared with the CAG, the latency was significantly increased and the number of errors was significantly reduced in the EAG, while the results for CSG were contrary. Mitochondrial unfolded protein reactions (UPRmt), mitochondrial autophagy, and mitochondrial protein import levels in each group of mice were detected using Q-PCR and Western blot experiments. Compared with the CNG, the UPRmt and mitochondrial autophagy levels in the CAG and ENG were significantly increased and the mitochondrial protein import levels were significantly reduced, while the results for the CSG were contrary. Compared with the ENG, the UPRmt and mitochondrial autophagy levels in the EAG were significantly increased and the mitochondrial protein import levels were significantly reduced, while the results for ESG were contrary. Compared with the CAG, the UPRmt and mitochondrial autophagy levels in the EAG were significantly increased and the mitochondrial protein import levels were significantly reduced, while the results for CSG were contrary. (4) Conclusions: Aerobic exercise can improve cognitive function levels and delay the symptoms of AD in APP/PS1 mice by regulating mitochondrial proteostasis.
    Keywords:  Alzheimer’s disease; aerobic exercise; mitochondrial autophagy; mitochondrial protein import; mitochondrial proteostasis; mitochondrial unfolded protein reaction
    DOI:  https://doi.org/10.3390/life13051204
  7. Int J Mol Sci. 2023 May 15. pii: 8763. [Epub ahead of print]24(10):
    Dysfunctional Autophagy, Proteostasis, and Mitochondria as a Prelude to Age-Related Macular Degeneration.
    Raji Rajesh Lenin, Yi Hui Koh, Zheting Zhang, Yan Zhuang Yeo, Bhav Harshad Parikh, Ivan Seah, Wendy Wong, Xinyi Su.
      Retinal pigment epithelial (RPE) cell dysfunction is a key driving force of AMD. RPE cells form a metabolic interface between photoreceptors and choriocapillaris, performing essential functions for retinal homeostasis. Through their multiple functions, RPE cells are constantly exposed to oxidative stress, which leads to the accumulation of damaged proteins, lipids, nucleic acids, and cellular organelles, including mitochondria. As miniature chemical engines of the cell, self-replicating mitochondria are heavily implicated in the aging process through a variety of mechanisms. In the eye, mitochondrial dysfunction is strongly associated with several diseases, including age-related macular degeneration (AMD), which is a leading cause of irreversible vision loss in millions of people globally. Aged mitochondria exhibit decreased rates of oxidative phosphorylation, increased reactive oxygen species (ROS) generation, and increased numbers of mitochondrial DNA mutations. Mitochondrial bioenergetics and autophagy decline during aging because of insufficient free radical scavenger systems, the impairment of DNA repair mechanisms, and reductions in mitochondrial turnover. Recent research has uncovered a much more complex role of mitochondrial function and cytosolic protein translation and proteostasis in AMD pathogenesis. The coupling of autophagy and mitochondrial apoptosis modulates the proteostasis and aging processes. This review aims to summarise and provide a perspective on (i) the current evidence of autophagy, proteostasis, and mitochondrial dysfunction in dry AMD; (ii) current in vitro and in vivo disease models relevant to assessing mitochondrial dysfunction in AMD, and their utility in drug screening; and (iii) ongoing clinical trials targeting mitochondrial dysfunction for AMD therapeutics.
    Keywords:  age-related macular degeneration; aging; autophagy; clinical trials; mitochondrial dysfunction; retinal pigment epithelium
    DOI:  https://doi.org/10.3390/ijms24108763
  8. Nature. 2023 May 24.
    Heteromeric clusters of ubiquitinated ER-shaping proteins drive ER-phagy.
    Hector Foronda, Yangxue Fu, Adriana Covarrubias-Pinto, Hartmut T Bocker, Alexis González, Eric Seemann, Patricia Franzka, Andrea Bock, Ramachandra M Bhaskara, Lutz Liebmann, Marina E Hoffmann, Istvan Katona, Nicole Koch, Joachim Weis, Ingo Kurth, Joseph G Gleeson, Fulvio Reggiori, Gerhard Hummer, Michael M Kessels, Britta Qualmann, Muriel Mari, Ivan Dikić, Christian A Hübner.
      Membrane-shaping proteins characterized by reticulon homology domains play an important part in the dynamic remodelling of the endoplasmic reticulum (ER). An example of such a protein is FAM134B, which can bind LC3 proteins and mediate the degradation of ER sheets through selective autophagy (ER-phagy)1. Mutations in FAM134B result in a neurodegenerative disorder in humans that mainly affects sensory and autonomic neurons2. Here we report that ARL6IP1, another ER-shaping protein that contains a reticulon homology domain and is associated with sensory loss3, interacts with FAM134B and participates in the formation of heteromeric multi-protein clusters required for ER-phagy. Moreover, ubiquitination of ARL6IP1 promotes this process. Accordingly, disruption of Arl6ip1 in mice causes an expansion of ER sheets in sensory neurons that degenerate over time. Primary cells obtained from Arl6ip1-deficient mice or from patients display incomplete budding of ER membranes and severe impairment of ER-phagy flux. Therefore, we propose that the clustering of ubiquitinated ER-shaping proteins facilitates the dynamic remodelling of the ER during ER-phagy and is important for neuronal maintenance.
    DOI:  https://doi.org/10.1038/s41586-023-06090-9
  9. Alzheimers Dement. 2023 May 22.
    Longitudinal changes in Alzheimer's-related plasma biomarkers and brain amyloid.
    Murat Bilgel, Yang An, Keenan A Walker, Abhay R Moghekar, Nicholas J Ashton, Przemysław R Kac, Thomas K Karikari, Kaj Blennow, Henrik Zetterberg, Bruno M Jedynak, Madhav Thambisetty, Luigi Ferrucci, Susan M Resnick.
      INTRODUCTION: Understanding longitudinal plasma biomarker trajectories relative to brain amyloid changes can help devise Alzheimer's progression assessment strategies.METHODS: We examined the temporal order of changes in plasma amyloid-β ratio ( A β 42 / A β 40 ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ ), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau ratios ( p-tau181 / A β 42 $\text{p-tau181}/\mathrm{A}{\beta}_{42}$ , p-tau231 / A β 42 $\text{p-tau231}/\mathrm{A}{\beta}_{42}$ ) relative to 11 C-Pittsburgh compound B (PiB) positron emission tomography (PET) cortical amyloid burden (PiB-/+). Participants (n = 199) were cognitively normal at index visit with a median 6.1-year follow-up.
    RESULTS: PiB groups exhibited different rates of longitudinal change in A β 42 / A β 40 ( β = 5.41 × 10 - 4 , SE = 1.95 × 10 - 4 , p = 0.0073 ) ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}\ ( {\beta \ = \ 5.41 \times {{10}}^{ - 4},{\rm{\ SE\ }} = \ 1.95 \times {{10}}^{ - 4},\ p\ = \ 0.0073} )$ . Change in brain amyloid correlated with change in GFAP (r = 0.5, 95% CI = [0.26, 0.68]). The greatest relative decline in A β 42 / A β 40 ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ (-1%/year) preceded brain amyloid positivity by 41 years (95% CI = [32, 53]).
    DISCUSSION: Plasma A β 42 / A β 40 ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ may begin declining decades prior to brain amyloid accumulation, whereas p-tau ratios, GFAP, and NfL increase closer in time. HIGHLIGHTS Plasma A β 42 / A β 40 ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ declines over time among PiB- but does not change among PiB+. Phosphorylated-tau to Aβ42 ratios increase over time among PiB+ but do not change among PiB-. Rate of change in brain amyloid is correlated with change in GFAP and neurofilament light chain. The greatest decline in A β 42 / A β 40 ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ may precede brain amyloid positivity by decades.
    Keywords:  Pittsburgh compound B; biomarkers; longitudinal; plasma; positron emission tomography
    DOI:  https://doi.org/10.1002/alz.13157
  10. Elife. 2023 May 23. pii: e85251. [Epub ahead of print]12
    Tau polarizes an aging transcriptional signature to excitatory neurons and glia.
    Timothy Wu, Jennifer M Deger, Hui Ye, Caiwei Guo, Justin Dhindsa, Brandon T Pekarek, Rami Al-Ouran, Zhandong Liu, Ismael Al-Ramahi, Juan Botas, Joshua M Shulman.
      Aging is a major risk factor for Alzheimer's disease (AD), and cell-type vulnerability underlies its characteristic clinical manifestations. We have performed longitudinal, single-cell RNA-sequencing in Drosophila with pan-neuronal expression of human tau, which forms AD neurofibrillary tangle pathology. Whereas tau- and aging-induced gene expression strongly overlap (93%), they differ in the affected cell types. In contrast to the broad impact of aging, tau-triggered changes are strongly polarized to excitatory neurons and glia. Further, tau can either activate or suppress innate immune gene expression signatures in a cell type-specific manner. Integration of cellular abundance and gene expression pinpoints Nuclear Factor Kappa B signaling in neurons as a marker for cellular vulnerability. We also highlight the conservation of cell type-specific transcriptional patterns between Drosophila and human postmortem brain tissue. Overall, our results create a resource for dissection of dynamic, age-dependent gene expression changes at cellular resolution in a genetically tractable model of tauopathy.
    Keywords:  D. melanogaster; genetics; genomics; human; neuroscience
    DOI:  https://doi.org/10.7554/eLife.85251
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