bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2021‒12‒05
thirteen papers selected by
Rich Giadone
Harvard University
  1. A Guide to Studying Protein Aggregation.
  2. Atlas of RNA editing events affecting protein expression in aged and Alzheimer's disease human brain tissue.
  3. ER-misfolded proteins become sequestered with mitochondria and impair mitochondrial function.
  4. CRYPTOCHROMES promote daily protein homeostasis.
  5. O-Glycosylation Induces Amyloid-β To Form New Fibril Polymorphs Vulnerable for Degradation.
  6. Role of AMPK mediated pathways in autophagy and aging.
  7. Peroxisomal support of mitochondrial respiratory efficiency promotes ER stress survival.
  8. Aging of the Hematopoietic Stem Cell Niche: New Tools to Answer an Old Question.
  9. ATF6-mediated unfolded protein response facilitates AAV2 transduction by releasing the suppression of AAV receptor on ER stress.
  10. Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy.
  11. The formation of small aggregates contributes to the neurotoxic effects of tau45-230.
  12. Klotho in kidney diseases: A crosstalk between the renin-angiotensin system and endoplasmic reticulum stress.
  13. Insights into the changes in the proteome of Alzheimer disease elucidated by a meta-analysis.
  1. FEBS J. 2021 Dec 04.
    A Guide to Studying Protein Aggregation.
    Joëlle A J Housmans, Guiqin Wu, Joost Schymkowitz, Frederic Rousseau.
      Disrupted protein folding or decreased protein stability can lead to the accumulation of (partially) un- or misfolded proteins, which ultimately cause the formation of protein aggregates. Much of the interest in protein aggregation is associated with its involvement in a wide range of human diseases and the challenges it poses for large-scale biopharmaceutical manufacturing and formulation of therapeutic proteins and peptides. On the other hand, protein aggregates can also be functional, as observed in nature, which triggered its use in the development of biomaterials or therapeutics as well as for the improvement of food characteristics. Thus, unmasking the various steps involved in protein aggregation is critical to obtain a better understanding of the underlying mechanism of amyloid formation. This knowledge will allow a more tailored development of diagnostic methods and treatments for amyloid-associated diseases, as well as applications in the fields of new (bio)materials, food technology and therapeutics. However, the complex and dynamic nature of the aggregation process makes the study of protein aggregation challenging. To provide guidance on how to analyze protein aggregation, in this review we summarize the most commonly investigated aspects of protein aggregation with some popular corresponding methods.
    Keywords:  Protein aggregation; aggregation kinetics; aggregation propensity; aggregation-prone region; amorphous aggregates; fibrils; protein homeostasis; protein stability; β-sheet
    DOI:  https://doi.org/10.1111/febs.16312
  2. Nat Commun. 2021 Dec 02. 12(1): 7035
    Atlas of RNA editing events affecting protein expression in aged and Alzheimer's disease human brain tissue.
    Yiyi Ma, Eric B Dammer, Daniel Felsky, Duc M Duong, Hans-Ulrich Klein, Charles C White, Maotian Zhou, Benjamin A Logsdon, Cristin McCabe, Jishu Xu, Minghui Wang, Thomas S Wingo, James J Lah, Bin Zhang, Julie Schneider, Mariet Allen, Xue Wang, Nilüfer Ertekin-Taner, Nicholas T Seyfried, Allan I Levey, David A Bennett, Philip L De Jager.
      RNA editing is a feature of RNA maturation resulting in the formation of transcripts whose sequence differs from the genome template. Brain RNA editing may be altered in Alzheimer's disease (AD). Here, we analyzed data from 1,865 brain samples covering 9 brain regions from 1,074 unrelated subjects on a transcriptome-wide scale to identify inter-regional differences in RNA editing. We expand the list of known brain editing events by identifying 58,761 previously unreported events. We note that only a small proportion of these editing events are found at the protein level in our proteome-wide validation effort. We also identified the occurrence of editing events associated with AD dementia, neuropathological measures and longitudinal cognitive decline in: SYT11, MCUR1, SOD2, ORAI2, HSDL2, PFKP, and GPRC5B. Thus, we present an extended reference set of brain RNA editing events, identify a subset that are found to be expressed at the protein level, and extend the narrative of transcriptomic perturbation in AD to RNA editing.
    DOI:  https://doi.org/10.1038/s41467-021-27204-9
  3. Commun Biol. 2021 Dec 02. 4(1): 1350
    ER-misfolded proteins become sequestered with mitochondria and impair mitochondrial function.
    Adrián Cortés Sanchón, Harshitha Santhosh Kumar, Matilde Mantovani, Ivan Osinnii, José María Mateos, Andres Kaech, Dimitri Shcherbakov, Rashid Akbergenov, Erik C Böttger.
      Proteostasis is a challenge for cellular organisms, as all known protein synthesis machineries are error-prone. Here we show by cell fractionation and microscopy studies that misfolded proteins formed in the endoplasmic reticulum can become associated with and partly transported into mitochondria, resulting in impaired mitochondrial function. Blocking the endoplasmic reticulum-mitochondria encounter structure (ERMES), but not the mitochondrial sorting and assembly machinery (SAM) or the mitochondrial surveillance pathway components Msp1 and Vms1, abrogated mitochondrial sequestration of ER-misfolded proteins. We term this mitochondria-associated proteostatic mechanism for ER-misfolded proteins ERAMS (ER-associated mitochondrial sequestration). We testify to the relevance of this pathway by using mutant α-1-antitrypsin as an example of a human disease-related misfolded ER protein, and we hypothesize that ERAMS plays a role in pathological features such as mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s42003-021-02873-w
  4. EMBO J. 2021 Nov 29. e2021108883
    CRYPTOCHROMES promote daily protein homeostasis.
    David C S Wong, Estere Seinkmane, Aiwei Zeng, Alessandra Stangherlin, Nina M Rzechorzek, Andrew D Beale, Jason Day, Martin Reed, Sew Y Peak-Chew, Christine T Styles, Rachel S Edgar, Marrit Putker, John S O'Neill.
      The daily organisation of most mammalian cellular functions is attributed to circadian regulation of clock-controlled protein expression, driven by daily cycles of CRYPTOCHROME-dependent transcriptional feedback repression. To test this, we used quantitative mass spectrometry to compare wild-type and CRY-deficient fibroblasts under constant conditions. In CRY-deficient cells, we found that temporal variation in protein, phosphopeptide, and K+ abundance was at least as great as wild-type controls. Most strikingly, the extent of temporal variation within either genotype was much smaller than overall differences in proteome composition between WT and CRY-deficient cells. This proteome imbalance in CRY-deficient cells and tissues was associated with increased susceptibility to proteotoxic stress, which impairs circadian robustness, and may contribute to the wide-ranging phenotypes of CRY-deficient mice. Rather than generating large-scale daily variation in proteome composition, we suggest it is plausible that the various transcriptional and post-translational functions of CRY proteins ultimately act to maintain protein and osmotic homeostasis against daily perturbation.
    Keywords:  CRYPTOCHROME; circadian rhythm; clock mutant; protein homeostasis; proteotoxic stress
    DOI:  https://doi.org/10.15252/embj.2021108883
  5. J Am Chem Soc. 2021 Nov 29.
    O-Glycosylation Induces Amyloid-β To Form New Fibril Polymorphs Vulnerable for Degradation.
    Dangliang Liu, Qijia Wei, Wencheng Xia, Changdong He, Qikai Zhang, Lu Huang, Xiaoya Wang, Yunpeng Sun, Yeyang Ma, Xiaohui Zhang, Yuan Wang, Xiaomeng Shi, Cong Liu, Suwei Dong.
      Brain accumulation of amyloid-β (Aβ) peptides (resulting from a disrupted balance between biosynthesis and clearance) occurs during the progression of Alzheimer's disease (AD). Aβ peptides have diverse posttranslational modifications (PTMs) that variously modulate Aβ aggregation into fibrils, but understanding the mechanistic roles of PTMs in these processes remains a challenge. Here, we chemically synthesized three homogeneously modified isoforms of Aβ (1-42) peptides bearing Tyr10 O-glycosylation, an unusual PTM initially identified from the cerebrospinal fluid samples of AD patients. We discovered that O-glycans significantly affect both the aggregation and degradation of Aβ42. By combining cryo-EM and various biochemical assays, we demonstrate that a Galβ1-3GalNAc modification redirects Aβ42 to form a new fibril polymorphic structure that is less stable and more vulnerable to Aβ-degrading enzymes (e.g., insulin-degrading enzyme). Thus, beyond showing how particular O-glycosylation modifications affect Aβ42 aggregation at the molecular level, our study provides powerful experimental tools to support further investigations about how PTMs affect Aβ42 fibril aggregation and AD-related neurotoxicity.
    DOI:  https://doi.org/10.1021/jacs.1c08607
  6. Biochimie. 2021 Nov 24. pii: S0300-9084(21)00271-6. [Epub ahead of print]
    Role of AMPK mediated pathways in autophagy and aging.
    Yuchen Ge, Min Zhou, Cui Chen, Xiaojian Wu, Xiaobo Wang.
      AMPK is an important kinase regulating energy homeostasis and also a key protein involved in a variety of signal transduction pathways. It plays a vitally regulatory role in cellular senescence. Activation of AMPK can delay or block the aging process, which is of great significance in the treatment of cardiovascular diseases and other aging related diseases, and provides a potential target for new indications such as Alzheimer's disease. Therefore, AMPK signaling pathway plays an important role in aging research. The in-depth study of AMPK activators will provide more new directions for the treatment of age-related maladies and the development of innovative drugs. Autophagy is a process that engulfs and degrades own cytoplasm or organelles. Thereby, meeting the metabolic demands and updating certain organelles of the cell has become a hotspot in the field of anti-aging in recent years. AMPK plays an important role between autophagy and senescence. In our review, the relationship among AMPK signaling, autophagy and aging will be clarified through the interaction between AMPK and mTOR, ULK1, FOXO, p53, SIRT1, and NF -κB.
    Keywords:  AMPK; Aging; Autophagy; Disease; Signaling pathways
    DOI:  https://doi.org/10.1016/j.biochi.2021.11.008
  7. J Cell Sci. 2021 Dec 02. pii: jcs.259254. [Epub ahead of print]
    Peroxisomal support of mitochondrial respiratory efficiency promotes ER stress survival.
    Imadeddin Hijazi, Emily Wang, Michelle Orozco, Sarah Pelton, Amy Chang.
      Endoplasmic reticulum stress (ERS) occurs when cellular demand for protein folding exceeds the capacity of the organelle. Adaptation and cell survival in response to ERS requires a critical contribution by mitochondria and peroxisomes. During ERS response, mitochondrial respiration increases to ameliorate reactive oxygen species (ROS) accumulation; we now show in yeast that peroxisome abundance also increases to promote an adaptive response. In pox1▵ cells, defective in peroxisomal ß oxidation of fatty acids, respiratory response to ERS is impaired, and ROS accrues. However, respiratory response to ERS is rescued, and ROS production is mitigated in pox1▵ cells by overexpression of Mpc1, the mitochondrial pyruvate carrier that provides another source of acetyl CoA to fuel the TCA cycle and oxidative phosphorylation. Using proteomics, select mitochondrial proteins were identified that undergo upregulation by ERS to remodel respiratory machinery. Several peroxisome-based proteins were also increased, corroborating the peroxisomal role in ERS adaptation. Finally, ERS stimulates assembly of respiratory complexes into higher order supercomplexes, underlying increased electron transfer efficiency. Our results highlight peroxisomal and mitochondrial support for ERS adaptation to favor cell survival.
    Keywords:  Endoplasmic reticulum; Mitochondria; Stress survival
    DOI:  https://doi.org/10.1242/jcs.259254
  8. Front Immunol. 2021 ;12 738204
    Aging of the Hematopoietic Stem Cell Niche: New Tools to Answer an Old Question.
    Francesca Matteini, Medhanie A Mulaw, M Carolina Florian.
      The hematopoietic stem cell (HSC) niche is a specialized microenvironment, where a complex and dynamic network of interactions across multiple cell types regulates HSC function. During the last years, it became progressively clearer that changes in the HSC niche are responsible for specific alterations of HSC behavior. The aging of the bone marrow (BM) microenvironment has been shown to critically contribute to the decline in HSC function over time. Interestingly, while upon aging some niche structures within the BM are degenerated and negatively affect HSC functionality, other niche cells and specific signals are preserved and essential to retaining HSC function and regenerative capacity. These new findings on the role of the aging BM niche critically depend on the implementation of new technical tools, developed thanks to transdisciplinary approaches, which bring together different scientific fields. For example, the development of specific mouse models in addition to coculture systems, new 3D-imaging tools, ossicles, and ex-vivo BM mimicking systems is highlighting the importance of new technologies to unravel the complexity of the BM niche on aging. Of note, an exponential impact in the understanding of this biological system has been recently brought by single-cell sequencing techniques, spatial transcriptomics, and implementation of artificial intelligence and deep learning approaches to data analysis and integration. This review focuses on how the aging of the BM niche affects HSCs and on the new tools to investigate the specific alterations occurring in the BM upon aging. All these new advances in the understanding of the BM niche and its regulatory function on HSCs have the potential to lead to novel therapeutical approaches to preserve HSC function upon aging and disease.
    Keywords:  HSC niche; aging; arteriolar niche; bone marrow imaging; deep learning; sinusoidal niche; vessel remodeling
    DOI:  https://doi.org/10.3389/fimmu.2021.738204
  9. J Virol. 2021 Dec 01. JVI0110321
    ATF6-mediated unfolded protein response facilitates AAV2 transduction by releasing the suppression of AAV receptor on ER stress.
    Mengtian Cui, Qingfang Zhao, Jing Wang, Yang Si, Shan Cheng, Wei Ding.
      Adeno-associated virus (AAV) is extensively used as a viral vector to deliver therapeutic genes during human gene therapy. A high affinity cellular receptor (AAVR) for most serotypes was recently identified, however, its biological function as a gene product remains unclear. In this study, we used AAVR knockdown cell models to show that AAVR depletion significantly attenuated cells to activate unfolded protein response (UPR) pathways, when exposed to the endoplasmic reticulum (ER) stress inducer, tunicamycin. By analyzing three major UPR pathways, we found that ATF6 signaling was most affected in an AAVR-dependent fashion, distinct to CHOP and XBP1 branches. AAVR capacity in UPR regulation required the full native AAVR protein, and AAV2 capsid binding to the receptor altered ATF6 dynamics. Conversely, the transduction efficiency of AAV2 was associated with changes in ATF6 signaling in host cells following treatment with different small molecules. Thus, AAVR served as an inhibitory molecule to repress UPR responses via a specificity for ATF6 signaling, and the AAV2 infection route involved the release from AAVR-mediated ATF6 repression, thereby facilitating viral intracellular trafficking and transduction. Importance The native function of the AAVR as an ER-Golgi localized protein is largely unknown. We showed that AAVR acted as a functional molecule to regulate UPR signaling under induced ER stress. AAVR inhibited the activation of the transcription factor, ATF6, whereas receptor binding to AAV2 released the suppression effects. This finding has expanded our understanding of AAV infection biology in terms of the physiological properties of AAVR in host cells. Importantly, our research provides a possible strategy which may improve the efficiency of AAV mediated gene delivery during gene therapy.
    DOI:  https://doi.org/10.1128/JVI.01103-21
  10. J Clin Invest. 2021 Nov 30. pii: e144983. [Epub ahead of print]
    Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy.
    Frank L van de Veerdonk, Giorgia Renga, Marilena Pariano, Marina M Bellet, Giuseppe Servillo, Francesca Fallarino, Antonella De Luca, Rossana G Iannitti, Danilo Piobbico, Marco Gargaro, Giorgia Manni, Fiorella D'Onofrio, Claudia Stincardini, Luigi Sforna, Monica Borghi, Marilena Castelli, Stefania Pieroni, Vasileios Oikonomou, Valeria R Villella, Matteo Puccetti, Stefano Giovagnoli, Roberta Galarini, Carolina Barola, Luigi Maiuri, Della-Fazia Maria Agnese, Barbara Cellini, Vincenzo Talesa, Charles A Dinarello, Claudio Costantini, Luigina Romani.
      Autophagy selectively degrades aggregation-prone misfolded proteins caused by defective cellular proteostasis. However, the complexity of autophagy may prevent the full appreciation of how its modulation could be used as a therapeutic strategy in disease management. Here we define a molecular pathway through which recombinant interleukin-1 receptor antagonist (IL-1Ra, anakinra) affects cellular proteostasis independently from the IL-1 receptor (IL-1R1). Anakinra promoted H2O2-driven autophagy through a xenobiotic sensing pathway involving the aryl hydrocarbon receptor that, activated through the indoleamine 2,3-dioxygenase 1-kynurenine pathway, transcriptionally activates NADPH Oxidase 4 independent of the IL-1R1. By coupling the mitochondrial redox balance to autophagy, anakinra improved the dysregulated proteostasis network in murine and human cystic fibrosis. We anticipate that anakinra may represent a therapeutic option in addition to its IL-1R1 dependent anti-inflammatory properties by acting at the intersection of mitochondrial oxidative stress and autophagy with the capacity to restore conditions in which defective proteostasis leads to human disease.
    Keywords:  Autophagy; Fungal infections; Infectious disease; Inflammation
    DOI:  https://doi.org/10.1172/JCI144983
  11. Neurochem Int. 2021 Nov 29. pii: S0197-0186(21)00298-9. [Epub ahead of print] 105252
    The formation of small aggregates contributes to the neurotoxic effects of tau45-230.
    Sana Afreen, Adriana Ferreira.
      Intracellular deposits of hyperphosphorylated tau are commonly detected in tauopathies. Furthermore, these aggregates seem to play an important role in the pathobiology of these diseases. In the present study, we determined whether the recently identified neurotoxic tau45-230 fragment also formed aggregates in neurodegenerative disorders. The presence of such aggregates was examined in brain samples obtained from Alzheimer's disease (AD) subjects by means of Western blot analysis performed under non-denaturing conditions. Our results showed that a mixture of tau45-230 oligomers of different sizes was easily detectable in brain samples obtained from AD subjects. Our data also suggested that tau45-230 oligomers could be internalized by cultured hippocampal neurons, mainly through a clathrin-mediated mechanism, triggering their degeneration. In addition, in vitro aggregation studies showed that tau45-230 modulated full-length tau aggregation thereby inducing the formation of smaller, and potentially more toxic, aggregates of this microtubule-associated protein. Together, these data identified alternative mechanisms underlying the toxic effects of tau45-230.
    Keywords:  Alzheimer's disease; Clathrin-mediated endocytosis; Neuronal degeneration; Tau(45-230) aggregates; tau(45-230) internalization
    DOI:  https://doi.org/10.1016/j.neuint.2021.105252
  12. Nephrol Dial Transplant. 2021 Nov 26. pii: gfab340. [Epub ahead of print]
    Klotho in kidney diseases: A crosstalk between the renin-angiotensin system and endoplasmic reticulum stress.
    Ajinath Kale, Himanshu Sankrityayan, Hans-Joachim Anders, Anil Bhanudas Gaikwad.
      Klotho is a transmembrane anti-ageing protein that exists in three forms, i.e., α-Klotho, β-Klotho, and γ-Klotho with distinct organ-specific expression and functions in the body. Here we focus on α-Klotho (mentioned as 'Klotho' only), abundantly expressed by the distal and proximal convoluted tubules of the kidney. Significant decline in systemic and renal Klotho level is a new hallmark for kidney disease progression. Emerging research portrays Klotho as a promising diagnostic as well as a therapeutic target for diabetic and non-diabetic kidney disease. Even so, the underlying mechanisms of Klotho regulation and the strategies to restore its systemic as well as the renal level are still lacking. Angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARBs) are the current standard of care for kidney diseases where the molecular mechanisms for their nephroprotective action are still ambiguous. Moreover, endoplasmic reticulum stress (ER stress) also plays a crucial role in kidney disease progression. Few studies have claimed that RAAS has a direct relation with ER stress generation and vice versa in kidney disease. Interestingly, RAAS and ER stress modulation is associated with Klotho regulation in kidney disease. Here we focus on how the RAAS and ER stress connects with Klotho regulation in kidney disease. We also discuss Klotho and ER stress in an alliance with the concept of hemodynamic and metabolic overload in kidney disease. In addition, we highlight novel approaches to implement Klotho as a therapeutic target via RAAS and ER stress modulation for the treatment of diabetic and non-diabetic kidney disease.
    Keywords:  ER stress; Klotho; hemodynamic and metabolic overload; kidney disease; renin-angiotensin system
    DOI:  https://doi.org/10.1093/ndt/gfab340
  13. Sci Data. 2021 Dec 03. 8(1): 312
    Insights into the changes in the proteome of Alzheimer disease elucidated by a meta-analysis.
    Hazal Haytural, Rui Benfeitas, Sophia Schedin-Weiss, Erika Bereczki, Melinda Rezeli, Richard D Unwin, Xusheng Wang, Eric B Dammer, Erik C B Johnson, Nicholas T Seyfried, Bengt Winblad, Betty M Tijms, Pieter Jelle Visser, Susanne Frykman, Lars O Tjernberg.
      Mass spectrometry (MS)-based proteomics is a powerful tool to explore pathogenic changes of a disease in an unbiased manner and has been used extensively in Alzheimer disease (AD) research. Here, by performing a meta-analysis of high-quality proteomic studies, we address which pathological changes are observed consistently and therefore most likely are of great importance for AD pathogenesis. We retrieved datasets, comprising a total of 21,588 distinct proteins identified across 857 postmortem human samples, from ten studies using labeled or label-free MS approaches. Our meta-analysis findings showed significant alterations of 757 and 1,195 proteins in AD in the labeled and label-free datasets, respectively. Only 33 proteins, some of which were associated with synaptic signaling, had the same directional change across the individual studies. However, despite alterations in individual proteins being different between the labeled and the label-free datasets, several pathways related to synaptic signaling, oxidative phosphorylation, immune response and extracellular matrix were commonly dysregulated in AD. These pathways represent robust changes in the human AD brain and warrant further investigation.
    DOI:  https://doi.org/10.1038/s41597-021-01090-8
This page is being maintained by Thomas Krichel. It was last updated on 2021‒12‒05 at 21:05:14.