bims-proarb 2022-08-28 papers

bims-proarb

Biomed News

on Proteostasis in aging and regenerative biology

Issue of 2022–08–28
twelve papers selected by
Rich Giadone, Harvard University

Hsp90: From Cellular to Organismal Proteostasis.
HSF1, Aging, and Neurodegeneration.
Emerging Roles for G-Quadruplexes in Proteostasis.
Proteostasis Deregulation in Neurodegeneration and Its Link with Stress Granules: Focus on the Scaffold and Ribosomal Protein RACK1.
ER, Mitochondria, and ISR Regulation by mt-HSP70 and ATF5 upon Procollagen Misfolding in Osteoblasts.
Accelerated neuronal aging in vitro ∼melting watch ∼.
Old blood for young mice.
Hyperactivation of the proteasome in Caenorhabditis elegans protects against proteotoxic stress and extends lifespan.
Effect of endoplasmic reticulum stress on human trophoblast cells: Survival triggering or catastrophe resulting in death.
Co-expression network analysis of human tau-transgenic mice reveals protein modules associated with tau-induced pathologies.
What makes functional amyloids work?
Old plasma dilution reduces human biological age: a clinical study.

Cells. 2022 Aug 10. pii: 2479. [Epub ahead of print]11(16):

Hsp90: From Cellular to Organismal Proteostasis.

Milán Somogyvári, Saba Khatatneh, Csaba Sőti.

  Assuring a healthy proteome is indispensable for survival and organismal health. Proteome disbalance and the loss of the proteostasis buffer are hallmarks of various diseases. The essential molecular chaperone Hsp90 is a regulator of the heat shock response via HSF1 and a stabilizer of a plethora of signaling proteins. In this review, we summarize the role of Hsp90 in the cellular and organismal regulation of proteome maintenance.

Keywords:  Hsp90; aging; cancer; chaperones; development; neurodegenerative disease; obesity; proteostasis; stress

DOI:  https://doi.org/10.3390/cells11162479
Adv Exp Med Biol. 2022 Aug 23.

HSF1, Aging, and Neurodegeneration.

Alice Y Liu, Conceição A Minetti, David P Remeta, Kenneth J Breslauer, Kuang Yu Chen.

  Heat shock factor 1 (HSF1) is a master transcription regulator that mediates the induction of heat shock protein chaperones for quality control (QC) of the proteome and maintenance of proteostasis as a protective mechanism in response to stress. Research in this particular area has accelerated dramatically over the past three decades following successful isolation, cloning, and characterization of HSF1. The intricate multi-protein complexes and transcriptional activation orchestrated by HSF1 are fundamental processes within the cellular QC machinery. Our primary focus is on the regulation and function of HSF1 in aging and neurodegenerative diseases (ND) which represent physiological and pathological states of dysfunction in protein QC. This chapter presents an overview of HSF1 structural, functional, and energetic properties in healthy cells while addressing the deterioration of HSF1 function viz-à-viz age-dependent and neuron-specific vulnerability to ND. We discuss the structural domains of HSF1 with emphasis on the intrinsically disordered regions and note that disease proteins associated with ND are often structurally disordered and exquisitely sensitive to changes in cellular environment as may occur during aging. We propose a hypothesis that age-dependent changes of the intrinsically disordered proteome likely hold answers to understand many of the functional, structural, and organizational changes of proteins and signaling pathways in aging - dysfunction of HSF1 and accumulation of disease protein aggregates in ND included.Structured AbstractsIntroduction: Heat shock factor 1 (HSF1) is a master transcription regulator that mediates the induction of heat shock protein chaperones for quality control (QC) of the proteome as a cyto-protective mechanism in response to stress. There is cumulative evidence of age-related deterioration of this QC mechanism that contributes to disease vulnerability.
OBJECTIVES: Herein we discuss the regulation and function of HSF1 as they relate to the pathophysiological changes of protein quality control in aging and neurodegenerative diseases (ND).
METHODS: We present an overview of HSF1 structural, functional, and energetic properties in healthy cells while addressing the deterioration of HSF1 function vis-à-vis age-dependent and neuron-specific vulnerability to neurodegenerative diseases.
RESULTS: We examine the impact of intrinsically disordered regions on the function of HSF1 and note that proteins associated with neurodegeneration are natively unstructured and exquisitely sensitive to changes in cellular environment as may occur during aging.
CONCLUSIONS: We put forth a hypothesis that age-dependent changes of the intrinsically disordered proteome hold answers to understanding many of the functional, structural, and organizational changes of proteins - dysfunction of HSF1 in aging and appearance of disease protein aggregates in neurodegenerative diseases included.

Keywords:  Aging; HSF1, Heat shock factor 1; HSP, heat shock protein family; Hsp, Specific heat shock protein; Intrinsically disordered proteome; Neurodegeneration; Protein homeostasis

DOI:  https://doi.org/10.1007/5584_2022_733
FEBS J. 2022 Aug 26.

Emerging Roles for G-Quadruplexes in Proteostasis.

Bryan B Guzman, Ahyun Son, Theodore J Litberg, Zijue Huang, Daniel Dominguez, Scott Horowitz.

  How nucleic acids interact with proteins, and how they affect protein folding, aggregation, and misfolding is a still-evolving area of research. Considerable effort is now focusing on a particular structure of RNA and DNA, G-quadruplexes, and their role in protein homeostasis and disease. In this State-of-the-Art Review, we track recent reports on how G-quadruplexes influence protein aggregation, proteolysis, phase separation, and protein misfolding diseases, and pose currently unanswered questions in the advance of this scientific field.

Keywords:  ALS; Alzheimer; Fragile X; aggregation; chaperone; proteostasis; quadruplex

DOI:  https://doi.org/10.1111/febs.16608
Cells. 2022 Aug 19. pii: 2590. [Epub ahead of print]11(16):

Proteostasis Deregulation in Neurodegeneration and Its Link with Stress Granules: Focus on the Scaffold and Ribosomal Protein RACK1.

Mirco Masi, Alessandro Attanzio, Marco Racchi, Benjamin Wolozin, Sofia Borella, Fabrizio Biundo, Erica Buoso.

  The role of protein misfolding, deposition, and clearance has been the dominant topic in the last decades of investigation in the field of neurodegeneration. The impairment of protein synthesis, along with RNA metabolism and RNA granules, however, are significantly emerging as novel potential targets for the comprehension of the molecular events leading to neuronal deficits. Indeed, defects in ribosome activity, ribosome stalling, and PQC-all ribosome-related processes required for proteostasis regulation-can contribute to triggering stress conditions and promoting the formation of stress granules (SGs) that could evolve in the formation of pathological granules, usually occurring during neurodegenerating effects. In this review, the interplay between proteostasis, mRNA metabolism, and SGs has been explored in a neurodegenerative context with a focus on Alzheimer's disease (AD), although some defects in these same mechanisms can also be found in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are discussed here. Finally, we highlight the role of the receptor for activated C kinase 1 (RACK1) in these pathologies and note that, besides its well characterized function as a scaffold protein, it has an important role in translation and can associate to stress granules (SGs) determining cell fate in response to diverse stress stimuli.

Keywords:  RACK1; RNA; neurodegeneration; proteostasis; stress granules; translation

DOI:  https://doi.org/10.3390/cells11162590
Adv Sci (Weinh). 2022 Aug 21. e2201273

ER, Mitochondria, and ISR Regulation by mt-HSP70 and ATF5 upon Procollagen Misfolding in Osteoblasts.

Laura Gorrell, Elena Makareeva, Shakib Omari, Satoru Otsuru, Sergey Leikin.

  Cellular response to protein misfolding underlies multiple diseases. Collagens are the most abundant vertebrate proteins, yet little is known about cellular response to misfolding of their procollagen precursors. Osteoblasts (OBs)-the cells that make bone-produce so much procollagen that it accounts for up to 40% of mRNAs in the cell, which is why bone bears the brunt of mutations causing procollagen misfolding in osteogenesis imperfecta (OI). The present study of a G610C mouse model of OI by multiple transcriptomic techniques provides first solid clues to how OBs respond to misfolded procollagen accumulation in the endoplasmic reticulum (ER) and how this response affects OB function. Surprisingly, misfolded procollagen escapes the quality control in the ER lumen and indirectly triggers the integrated stress response (ISR) through other cell compartments. In G610C OBs, the ISR is regulated by mitochondrial HSP70 (mt-HSP70) and ATF5 instead of their BIP and ATF4 paralogues, which normally activate and regulate ISR to secretory protein misfolding in the ER. The involvement of mt-HSP70 and ATF5 together with other transcriptomic findings suggest that mitochondria might initiate the ISR upon disruption of ER-mitochondria connections or might respond to the ISR activated by a yet unknown sensor.

Keywords:  ATF5; HSPA9/mt-Hsp70/GRP75; cell stress; collagen; osteoblast; osteogenesis imperfecta

DOI:  https://doi.org/10.1002/advs.202201273
Front Aging Neurosci. 2022 ;14 868770

Accelerated neuronal aging in vitro ∼melting watch ∼.

Emi Inagaki, Sho Yoshimatsu, Hideyuki Okano.

  In developed countries, the aging of the population and the associated increase in age-related diseases are causing major unresolved medical, social, and environmental matters. Therefore, research on aging has become one of the most important and urgent issues in life sciences. If the molecular mechanisms of the onset and progression of neurodegenerative diseases are elucidated, we can expect to develop disease-modifying methods to prevent neurodegeneration itself. Since the discovery of induced pluripotent stem cells (iPSCs), there has been an explosion of disease models using disease-specific iPSCs derived from patient-derived somatic cells. By inducing the differentiation of iPSCs into neurons, disease models that reflect the patient-derived pathology can be reproduced in culture dishes, and are playing an active role in elucidating new pathological mechanisms and as a platform for new drug discovery. At the same time, however, we are faced with a new problem: how to recapitulate aging in culture dishes. It has been pointed out that cells differentiated from pluripotent stem cells are juvenile, retain embryonic traits, and may not be fully mature. Therefore, attempts are being made to induce cell maturation, senescence, and stress signals through culture conditions. It has also been reported that direct conversion of fibroblasts into neurons can reproduce human neurons with an aged phenotype. Here, we outline some state-of-the-art insights into models of neuronal aging in vitro. New frontiers in which stem cells and methods for inducing differentiation of tissue regeneration can be applied to aging research are just now approaching, and we need to keep a close eye on them. These models are forefront and intended to advance our knowledge of the molecular mechanisms of aging and contribute to the development of novel therapies for human neurodegenerative diseases associated with aging.

Keywords:  aging; disease modeling; human model; iPSCs (induced pluripotent stem cells); in vitro model

DOI:  https://doi.org/10.3389/fnagi.2022.868770
Lab Anim (NY). 2022 Sep;51(9): 238

Old blood for young mice.

Alexandra Le Bras.

DOI: https://doi.org/10.1038/s41684-022-01044-6
J Biol Chem. 2022 Aug 22. pii: S0021-9258(22)00858-4. [Epub ahead of print] 102415

Hyperactivation of the proteasome in Caenorhabditis elegans protects against proteotoxic stress and extends lifespan.

Raymond T Anderson, Thomas A Bradley, David M Smith.

  Virtually all age-related neurodegenerative diseases (NDs) can be characterized by the accumulation of proteins inside and outside the cell that are thought to significantly contribute to disease pathogenesis. One of the cell's primary systems for the degradation of misfolded/damaged proteins is the Ubiquitin Proteasome System (UPS), and its impairment is implicated in essentially all NDs. Thus, upregulating this system to combat NDs has garnered a great deal of interest in recent years. Various animal models have focused on stimulating 26S activity and increasing 20S proteasome levels, but thus far, none have targeted intrinsic activation of the 20S proteasome itself. Therefore, we constructed an animal model that endogenously expresses a hyperactive, open-gate proteasome in Caenorhabditis elegans (C. elegans). The gate-destabilizing mutation that we introduced into the nematode germline yielded a viable nematode population with enhanced proteasomal activity, including peptide, unstructured protein, and ubiquitin-dependent degradation activities. We determined these nematodes showed a significantly increased lifespan and substantial resistance to oxidative and proteotoxic stress but a significant decrease in fecundity. Our results show that introducing a constitutively active proteasome into a multicellular organism is feasible and suggests targeting the proteasome gating mechanism as a valid approach for future age-related disease research efforts in mammals.

Keywords:  Aging; Caenorhabditis elegans (C. elegans); Enzyme kinetics; Oxidative stress; Proteasome; Protein degradation; Proteotoxic stress; Toxicity; Ubiquitin

DOI:  https://doi.org/10.1016/j.jbc.2022.102415
Acta Histochem. 2022 Aug 20. pii: S0065-1281(22)00110-6. [Epub ahead of print]124(7): 151951

Effect of endoplasmic reticulum stress on human trophoblast cells: Survival triggering or catastrophe resulting in death.

Gurur Garip, Berrin Ozdil, Duygu Kocaturk-Calik, Fatih Oltulu, Fatma Zuhal Eroglu, Huseyin Aktug, Aysegul Uysal.

Endoplasmic reticulum (ER) stress has been reported to play a role in the pathogenesis of intrauterine growth retardation and preeclampsia, especially implantation failure. Although in vitro ER stress studies in human trophoblast cell line have been conducted in recent years, the influence of Thapsigargin on intracellular dynamics on calcium homeostasis has not been proven. Here, the effects of ER stress and impaired calcium homeostasis on apoptosis, autophagy, cytoskeleton, hypoxia, and adhesion molecules in 2D and spheroid cultures of human trophectoderm cells were investigated at gene expression and protein levels. Thapsigargin caused ER stress by increasing GRP78 gene expression and protein levels. Human trophectoderm cells displayed different characterization properties in 2D and spheroids. While it moves in the pathway of EIF2A and IRE1A mechanisms in 2D, it proceeds in the pathway of EIF2A and ATF6 mechanisms in spheroids and triggers different responses in survival and programmed cell death mechanisms such as apoptosis and autophagy. This led to changes in the cytoskeleton, cell adhesion molecules and cell-cell interactions by affecting the hypoxia mechanism.

DOI: https://doi.org/10.1016/j.acthis.2022.151951
iScience. 2022 Aug 19. 25(8): 104832

Co-expression network analysis of human tau-transgenic mice reveals protein modules associated with tau-induced pathologies.

Kazuya Tsumagari, Yoshiaki Sato, Aki Shimozawa, Hirofumi Aoyagi, Hideyuki Okano, Junro Kuromitsu.

  Abnormally accumulated tau protein aggregates are one of the hallmarks of neurodegenerative diseases, including Alzheimer's disease (AD). In order to investigate proteomic alteration driven by tau aggregates, we implemented quantitative proteomics to analyze disease model mice expressing human MAPT P301S transgene (hTau-Tg) and quantified more than 9,000 proteins in total. We applied the weighted gene co-expression analysis (WGCNA) algorithm to the datasets and explored protein co-expression modules that were associated with the accumulation of tau aggregates and were preserved in proteomes of AD brains. This led us to identify four modules with functions related to neuroinflammatory responses, mitochondrial energy production processes (including the tricarboxylic acid cycle and oxidative phosphorylation), cholesterol biosynthesis, and postsynaptic density. Furthermore, a phosphoproteomics study uncovered phosphorylation sites that were highly correlated with these modules. Our datasets represent resources for understanding the molecular basis of tau-induced neurodegeneration, including AD.

Keywords:  Molecular biology; omics; proteomics

DOI:  https://doi.org/10.1016/j.isci.2022.104832
Crit Rev Biochem Mol Biol. 2022 Aug 23. 1-13

What makes functional amyloids work?

Ansgar B Siemer.

  Although first described in the context of disease, cross-β (amyloid) fibrils have also been found as functional entities in all kingdoms of life. However, what are the specific properties of the cross-β fibril motif that convey biological function, make them especially suited for their particular purpose, and distinguish them from other fibrils found in biology? This review approaches these questions by arguing that cross-β fibrils are highly periodic, stable, and self-templating structures whose formation is accompanied by substantial conformational change that leads to a multimerization of their core and framing sequences. A discussion of each of these properties is followed by selected examples of functional cross-β fibrils that show how function is usually achieved by leveraging many of these properties.

Keywords:  Functional amyloid; cross-β motif; protein aggregation; protein fibrils; structure–function relationship

DOI:  https://doi.org/10.1080/10409238.2022.2113030
Geroscience. 2022 Aug 24.

Old plasma dilution reduces human biological age: a clinical study.

Daehwan Kim, Dobri D Kiprov, Connor Luellen, Michael Lieb, Chao Liu, Etsuko Watanabe, Xiaoyue Mei, Kaitlin Cassaleto, Joel Kramer, Michael J Conboy, Irina M Conboy.

  This work extrapolates to humans the previous animal studies on blood heterochronicity and establishes a novel direct measurement of biological age. Our results support the hypothesis that, similar to mice, human aging is driven by age-imposed systemic molecular excess, the attenuation of which reverses biological age, defined in our work as a deregulation (noise) of 10 novel protein biomarkers. The results on biological age are strongly supported by the data, which demonstrates that rounds of therapeutic plasma exchange (TPE) promote a global shift to a younger systemic proteome, including youthfully restored pro-regenerative, anticancer, and apoptotic regulators and a youthful profile of myeloid/lymphoid markers in circulating cells, which have reduced cellular senescence and lower DNA damage. Mechanistically, the circulatory regulators of the JAK-STAT, MAPK, TGF-beta, NF-κB, and Toll-like receptor signaling pathways become more youthfully balanced through normalization of TLR4, which we define as a nodal point of this molecular rejuvenation. The significance of our findings is confirmed through big-data gene expression studies.

Keywords:  Aging; Biological noise; Lymphoid/myeloid markers; Plasmapheresis; Proteomics; Rejuvenation

DOI:  https://doi.org/10.1007/s11357-022-00645-w