bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2022‒10‒09
fifteen papers selected by
Rich Giadone
Harvard University
  1. Roles of constitutively secreted extracellular chaperones in neuronal cell repair and regeneration.
  2. Age-dependent aggregation of ribosomal RNA-binding proteins links deterioration in chromatin stability with challenges to proteostasis.
  3. [The role of unfolded protein responses in hematopoiesis].
  4. A brain atlas of synapse protein lifetime across the mouse lifespan.
  5. The use of pharmacological chaperones in rare diseases caused by reduced protein stability.
  6. Proteinopathies: Deciphering Physiology and Mechanisms to Develop Effective Therapies for Neurodegenerative Diseases.
  7. In vivo stress reporters as early biomarkers of the cellular changes associated with progeria.
  8. New insights into the interplay between autophagy and oxidative and endoplasmic reticulum stress in neuronal cell death and survival.
  9. Aging RNA granule dynamics in neurodegeneration.
  10. A perturbed network in neurodegeneration.
  11. Aging compromises human islet beta cell function and identity by decreasing transcription factor activity and inducing ER stress.
  12. Editorial: Current advances in genetic dementia and aging.
  13. The Mitochondrial Unfolded Protein Response: A Novel Protective Pathway Targeting Cardiomyocytes.
  14. C-terminal fragment of APP interacts with p62, forms an aggregate, and induces autophagic degradation in Alzheimer's cell model.
  15. Heat Shock-Induced Extracellular Vesicles Derived from Neural Stem Cells Confer Marked Neuroprotection Against Oxidative Stress and Amyloid-β-Caused Neurotoxicity.
  1. Neural Regen Res. 2023 Apr;18(4): 769-772
    Roles of constitutively secreted extracellular chaperones in neuronal cell repair and regeneration.
    Sandeep Satapathy, Mark R Wilson.
      Protein quality control involves many processes that jointly act to regulate the expression, localization, turnover, and degradation of proteins, and has been highlighted in recent studies as critical to the differentiation of stem cells during regeneration. The roles of constitutively secreted extracellular chaperones in neuronal injury and disease are poorly understood. Extracellular chaperones are multifunctional proteins expressed by many cell types, including those of the nervous system, known to facilitate protein quality control processes. These molecules exert pleiotropic effects and have been implicated as playing important protective roles in a variety of stress conditions, including tissue damage, infections, and local tissue inflammation. This article aims to provide a critical review of what is currently known about the functions of extracellular chaperones in neuronal repair and regeneration and highlight future directions for this important research area. We review what is known of four constitutively secreted extracellular chaperones directly implicated in processes of neuronal damage and repair, including transthyretin, clusterin, α2-macroglobulin, and neuroserpin, and propose that investigation into the effects of these and other extracellular chaperones on neuronal repair and regeneration has the potential to yield valuable new therapies.
    Keywords:  cell viability; clusterin; extracellular chaperones; inflammation; neuroserpin; protein misfolding; transthyretin; α2-macroglobulin
    DOI:  https://doi.org/10.4103/1673-5374.353483
  2. Elife. 2022 Oct 04. pii: e75978. [Epub ahead of print]11
    Age-dependent aggregation of ribosomal RNA-binding proteins links deterioration in chromatin stability with challenges to proteostasis.
    Julie Paxman, Zhen Zhou, Richard O'Laughlin, Yuting Liu, Yang Li, Wanying Tian, Hetian Su, Yanfei Jiang, Shayna E Holness, Elizabeth Stasiowski, Lev S Tsimring, Lorraine Pillus, Jeff Hasty, Nan Hao.
      Chromatin instability and protein homeostasis (proteostasis) stress are two well-established hallmarks of aging, which have been considered largely independent of each other. Using microfluidics and single-cell imaging approaches, we observed that, during the replicative aging of S. cerevisiae, a challenge to proteostasis occurs specifically in the fraction of cells with decreased stability within the ribosomal DNA (rDNA). A screen of 170 yeast RNA-binding proteins identified ribosomal RNA (rRNA)-binding proteins as the most enriched group that aggregate upon a decrease in rDNA stability induced by inhibition of a conserved lysine deacetylase Sir2. Further, loss of rDNA stability induces age-dependent aggregation of rRNA-binding proteins through aberrant overproduction of rRNAs. These aggregates contribute to age-induced proteostasis decline and limit cellular lifespan. Our findings reveal a mechanism underlying the interconnection between chromatin instability and proteostasis stress and highlight the importance of cell-to-cell variability in aging processes.
    Keywords:  S. cerevisiae; cell biology; computational biology; systems biology
    DOI:  https://doi.org/10.7554/eLife.75978
  3. Rinsho Ketsueki. 2022 ;63(9): 1006-1013
    [The role of unfolded protein responses in hematopoiesis].
    Kenichi Miharada.
      Protein production is tightly regulated in cells because the accumulation of un-/misfolded proteins triggers cellular responses, particularly in the endoplasmic reticulum (ER). Recently, several studies have reported the implications of unfolded protein response (UPR) and ER stress in hematopoiesis, particularly in hematopoietic stem cells (HSCs). The majority of HSCs are maintained in a dormant state under physiological conditions in the adult body, and their protein synthesis rate is also maintained at a low level. Once HSC proliferation is activated, the protein synthesis rate is elevated, and therefore, newly synthesized peptides have to be efficiently folded to prevent the induction of UPR. Importantly, UPR can expand the ER capacity that enables increased protein production and eliminates cells accumulating abnormal proteins; thus, blocking the UPR signal could rather be hazardous for the cells. Thus, understanding how protein quality control is properly controlled and developing methods to manipulate the regulatory mechanisms are imperative to maximize the potential role of HSC.
    Keywords:  Bile acid; Endoplasmic reticulum stress; Hematopoietic stem cells; Unfolded protein response
    DOI:  https://doi.org/10.11406/rinketsu.63.1006
  4. Neuron. 2022 Sep 28. pii: S0896-6273(22)00814-5. [Epub ahead of print]
    A brain atlas of synapse protein lifetime across the mouse lifespan.
    Edita Bulovaite, Zhen Qiu, Maximilian Kratschke, Adrianna Zgraj, David G Fricker, Eleanor J Tuck, Ragini Gokhale, Babis Koniaris, Shekib A Jami, Paula Merino-Serrais, Elodie Husi, Lorena Mendive-Tapia, Marc Vendrell, Thomas J O'Dell, Javier DeFelipe, Noboru H Komiyama, Anthony Holtmaat, Erik Fransén, Seth G N Grant.
      The lifetime of proteins in synapses is important for their signaling, maintenance, and remodeling, and for memory duration. We quantified the lifetime of endogenous PSD95, an abundant postsynaptic protein in excitatory synapses, at single-synapse resolution across the mouse brain and lifespan, generating the Protein Lifetime Synaptome Atlas. Excitatory synapses have a wide range of PSD95 lifetimes extending from hours to several months, with distinct spatial distributions in dendrites, neurons, and brain regions. Synapses with short protein lifetimes are enriched in young animals and in brain regions controlling innate behaviors, whereas synapses with long protein lifetimes accumulate during development, are enriched in the cortex and CA1 where memories are stored, and are preferentially preserved in old age. Synapse protein lifetime increases throughout the brain in a mouse model of autism and schizophrenia. Protein lifetime adds a further layer to synapse diversity and enriches prevailing concepts in brain development, aging, and disease.
    Keywords:  HaloTag; aging; autism; brain development; dendritic spine; postsynaptic density; protein turnover; proteostasis; pyramidal neuron; synapse proteome; synaptome
    DOI:  https://doi.org/10.1016/j.neuron.2022.09.009
  5. Proteomics. 2022 Oct 07. e2200222
    The use of pharmacological chaperones in rare diseases caused by reduced protein stability.
    Jon Gil-Martínez, Ganeko Bernardo-Seisdedos, José M Mato, Oscar Millet.
      Rare diseases are most often caused by inherited genetic disorders that, after translation, will result in a protein with altered function. Decreased protein stability is the most frequent mechanism associated with a congenital pathogenic missense mutation and it implies the destabilization of the folded conformation in favor of unfolded or misfolded states. In the cellular context and when experimental data is available, a mutant protein with altered thermodynamic stability often also results in impaired homeostasis, with the deleterious accumulation of protein aggregates, metabolites and/or metabolic by-products. In the last decades a significant effort has enabled the characterization of rare diseases associated to protein stability defects and triggered the development of innovative therapeutic intervention lines, say, the use of pharmacological chaperones to correct the intracellular impaired homeostasis. In here, we review the current knowledge on rare diseases caused by reduced protein stability, paying special attention to the thermodynamic aspects of the protein destabilization, also focusing on some examples where pharmacological chaperones are being tested. This article is protected by copyright. All rights reserved.
    Keywords:  Missense mutation; pharmacological chaperones; protein stability; proteostasis; rare diseases
    DOI:  https://doi.org/10.1002/pmic.202200222
  6. Mol Neurobiol. 2022 Oct 07.
    Proteinopathies: Deciphering Physiology and Mechanisms to Develop Effective Therapies for Neurodegenerative Diseases.
    Gouri Chopra, Shabnam Shabir, Sumaira Yousuf, Simran Kauts, Shahnawaz A Bhat, Ashiq H Mir, Mahendra P Singh.
      Neurodegenerative diseases (NDs) are a cluster of diseases marked by progressive neuronal loss, axonal transport blockage, mitochondrial dysfunction, oxidative stress, neuroinflammation, and aggregation of misfolded proteins. NDs are more prevalent beyond the age of 50, and their symptoms often include motor and cognitive impairment. Even though various proteins are involved in different NDs, the mechanisms of protein misfolding and aggregation are very similar. Recently, several studies have discovered that, like prions, these misfolded proteins have the inherent capability of translocation from one neuron to another, thus having far-reaching implications for understanding the processes involved in the onset and progression of NDs, as well as the development of innovative therapy and diagnostic options. These misfolded proteins can also influence the transcription of other proteins and form aggregates, tangles, plaques, and inclusion bodies, which then accumulate in the CNS, leading to neuronal dysfunction and neurodegeneration. This review demonstrates protein misfolding and aggregation in NDs, and similarities and differences between different protein aggregates have been discussed. Furthermore, we have also reviewed the disposal of protein aggregates, the various molecular machinery involved in the process, their regulation, and how these molecular mechanisms are targeted to build innovative therapeutic and diagnostic procedures. In addition, the landscape of various therapeutic interventions for targeting protein aggregation for the effective prevention or treatment of NDs has also been discussed.
    Keywords:  Aggregates; Chaperone; Heat shock proteins; Misfolded protein; Neurodegenerative diseases
    DOI:  https://doi.org/10.1007/s12035-022-03042-8
  7. J Cell Mol Med. 2022 Oct 06.
    In vivo stress reporters as early biomarkers of the cellular changes associated with progeria.
    Francisco Inesta-Vaquera, Florian Weiland, Colin J Henderson, Charles Roland Wolf.
      Age-related diseases account for a high proportion of the total global burden of disease. Despite recent advances in understanding their molecular basis, there is a lack of suitable early biomarkers to test selected compounds and accelerate their translation to clinical trials. We have investigated the utility of in vivo stress reporter systems as surrogate early biomarkers of the degenerative disease progression. We hypothesized that cellular stress observed in models of human degenerative disease preceded overt cellular damage and at the same time will identify potential cytoprotective pathways. To test this hypothesis, we generated novel accelerated ageing (progeria) reporter mice by crossing the LmnaG609G mice into our oxidative stress/inflammation (Hmox1) and DNA damage (p21) stress reporter models. Histological analysis of reporter expression demonstrated a time-dependent and tissue-specific activation of the reporters in tissues directly associated with Progeria, including smooth muscle cells, the vasculature and gastrointestinal tract. Importantly, reporter expression was detected prior to any perceptible deleterious phenotype. Reporter expression can therefore be used as an early marker of progeria pathogenesis and to test therapeutic interventions. This work also demonstrates the potential to use stress reporter approaches to study and find new treatments for other degenerative diseases.
    Keywords:  accelerated ageing; early biomarker; preclinical model; progeria; stress pathways
    DOI:  https://doi.org/10.1111/jcmm.17574
  8. Front Cell Dev Biol. 2022 ;10 994037
    New insights into the interplay between autophagy and oxidative and endoplasmic reticulum stress in neuronal cell death and survival.
    Yahao Gao, Changshui Wang, Di Jiang, Gang An, Feng Jin, Junchen Zhang, Guangkui Han, Changmeng Cui, Pei Jiang.
      Autophagy is a dynamic process that maintains the normal homeostasis of cells by digesting and degrading aging proteins and damaged organelles. The effect of autophagy on neural tissue is still a matter of debate. Some authors suggest that autophagy has a protective effect on nerve cells, whereas others suggest that autophagy also induces the death of nerve cells and aggravates nerve injury. In mammals, oxidative stress, autophagy and endoplasmic reticulum stress (ERS) constitute important defense mechanisms to help cells adapt to and survive the stress conditions caused by physiological and pathological stimuli. Under many pathophysiological conditions, oxidative stress, autophagy and ERS are integrated and amplified in cells to promote the progress of diseases. Over the past few decades, oxidative stress, autophagy and ERS and their interactions have been a hot topic in biomedical research. In this review, we summarize recent advances in understanding the interactions between oxidative stress, autophagy and ERS in neuronal cell death and survival.
    Keywords:  autophagy; endoplasmic reticulum stress; neuronal cell death; neuronal cell injury; neuronal cell survival; oxidative stress
    DOI:  https://doi.org/10.3389/fcell.2022.994037
  9. Front Mol Biosci. 2022 ;9 991641
    Aging RNA granule dynamics in neurodegeneration.
    Kevin Rhine, Norah Al-Azzam, Tao Yu, Gene W Yeo.
      Disordered RNA-binding proteins and repetitive RNA sequences are the main genetic causes of several neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington's disease. Importantly, these components also seed the formation of cytoplasmic liquid-like granules, like stress granules and P bodies. Emerging evidence demonstrates that healthy granules formed via liquid-liquid phase separation can mature into solid- or gel-like inclusions that persist within the cell. These solidified inclusions are a precursor to the aggregates identified in patients, demonstrating that dysregulation of RNA granule biology is an important component of neurodegeneration. Here, we review recent literature highlighting how RNA molecules seed proteinaceous granules, the mechanisms of healthy turnover of RNA granules in cells, which biophysical properties underly a transition to solid- or gel-like material states, and why persistent granules disrupt the cellular homeostasis of neurons. We also identify various methods that will illuminate the contributions of disordered proteins and RNAs to neurodegeneration in ongoing research efforts.
    Keywords:  RNA; RNA granules; liquid-liquid phase separation; neurodegeneration; stress granules
    DOI:  https://doi.org/10.3389/fmolb.2022.991641
  10. Science. 2022 Oct 07. 378(6615): 28-29
    A perturbed network in neurodegeneration.
    Jean-Marc Gallo, Dieter Edbauer.
      Three proteins act in concert to cause neuronal pathology.
    DOI:  https://doi.org/10.1126/science.ade4210
  11. Sci Adv. 2022 Oct 07. 8(40): eabo3932
    Aging compromises human islet beta cell function and identity by decreasing transcription factor activity and inducing ER stress.
    Shristi Shrestha, Galina Erikson, James Lyon, Aliya F Spigelman, Austin Bautista, Jocelyn E Manning Fox, Cristiane Dos Santos, Maxim Shokhirev, Jean-Philippe Cartailler, Martin W Hetzer, Patrick E MacDonald, Rafael Arrojo E Drigo.
      Pancreatic islet beta cells are essential for maintaining glucose homeostasis. To understand the impact of aging on beta cells, we performed meta-analysis of single-cell RNA sequencing datasets, transcription factor (TF) regulon analysis, high-resolution confocal microscopy, and measured insulin secretion from nondiabetic donors spanning most of the human life span. This revealed the range of molecular and functional changes that occur during beta cell aging, including the transcriptional deregulation that associates with cellular immaturity and reorganization of beta cell TF networks, increased gene transcription rates, and reduced glucose-stimulated insulin release. These alterations associate with activation of endoplasmic reticulum (ER) stress and autophagy pathways. We propose that a chronic state of ER stress undermines old beta cell structure function to increase the risk of beta cell failure and type 2 diabetes onset as humans age.
    DOI:  https://doi.org/10.1126/sciadv.abo3932
  12. Front Aging Neurosci. 2022 ;14 1020547
    Editorial: Current advances in genetic dementia and aging.
    Yuzhen Xu, Daojun Hong, Ulises Gomez-Pinedo, Jun Liu, Jun Xu.
      
    Keywords:  Alzheimer's disease (AD); Aβ/tau; dementia; neuroimaging; polygenic
    DOI:  https://doi.org/10.3389/fnagi.2022.1020547
  13. Oxid Med Cell Longev. 2022 ;2022 6430342
    The Mitochondrial Unfolded Protein Response: A Novel Protective Pathway Targeting Cardiomyocytes.
    Jinfeng Liu, Xinyong He, Sicheng Zheng, Aisong Zhu, Junyan Wang.
      Mitochondrial protein homeostasis in cardiomyocyte injury determines not only the normal operation of mitochondrial function but also the fate of mitochondria in cardiomyocytes. Studies of mitochondrial protein homeostasis have become an integral part of cardiovascular disease research. Modulation of the mitochondrial unfolded protein response (UPRmt), a protective factor for cardiomyocyte mitochondria, may in the future become an important treatment strategy for myocardial protection in cardiovascular disease. However, because of insufficient understanding of the UPRmt and inadequate elucidation of relevant mechanisms, few therapeutic drugs targeting the UPRmt have been developed. The UPRmt maintains a series of chaperone proteins and proteases and is activated when misfolded proteins accumulate in the mitochondria. Mitochondrial injury leads to metabolic dysfunction in cardiomyocytes. This paper reviews the relationship of the UPRmt and mitochondrial quality monitoring with cardiomyocyte protection. This review mainly introduces the regulatory mechanisms of the UPRmt elucidated in recent years and the relationship between the UPRmt and mitophagy, mitochondrial fusion/fission, mitochondrial biosynthesis, and mitochondrial energy metabolism homeostasis in order to generate new ideas for the study of the mitochondrial protein homeostasis mechanisms as well as to provide a reference for the targeted drug treatment of imbalances in mitochondrial protein homeostasis following cardiomyocyte injury.
    DOI:  https://doi.org/10.1155/2022/6430342
  14. Am J Physiol Cell Physiol. 2022 Oct 03.
    C-terminal fragment of APP interacts with p62, forms an aggregate, and induces autophagic degradation in Alzheimer's cell model.
    Keigo Tanaka, Kohei Kuramoto, Tadashi Nakagawa, Yasuyuki Nomura, Koichiro Ozawa, Toru Hosoi.
      Alzheimer's disease is an intractable disease, and the accumulation of amyloid β in the brain is thought to be involved in the onset of the disease. Additionally, abnormal protein accumulation due to autophagic deficiency may also be involved in disease progression. Autophagy involves a mechanism called selective autophagy. However, the relationship between selective autophagy and the amyloid precursor protein (APP) remains unclear. In the present study, we analyzed the interaction between p62, an adapter protein, and an APP-related molecule, and found that p62 interacted with the C-terminal fragment of APP (C60). When C60 and p62 are overexpressed, aggregates are formed, and C60 is degraded by autophagy. These aggregates cannot be easily degraded, even with a reducing agent. We also found that autophagosome- and lysosome-marker-positive vesicles were formed in the C60- and p62-expressing cells. Super resolution technology also revealed that p62-C60-positive autophagosomes were formed in the cells. Overall, these results suggest that p62 may bind with C60 to form aggregates and induce autophagy in autophagosomes. These results reveal one of the mechanisms underlying the progression of Alzheimer's disease, in which selective autophagy may be involved.
    Keywords:  APP transmembrane C-terminal fragments (CTFs); Alzheimer's disease; amyloid precursor protein (APP); autophagy; p62 (sequestosome 1(SQSTM1))
    DOI:  https://doi.org/10.1152/ajpcell.00003.2022
  15. Mol Neurobiol. 2022 Oct 03.
    Heat Shock-Induced Extracellular Vesicles Derived from Neural Stem Cells Confer Marked Neuroprotection Against Oxidative Stress and Amyloid-β-Caused Neurotoxicity.
    Christa C Huber, Eduardo A Callegari, Maria D Paez, Svetlana Romanova, Hongmin Wang.
      Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and a leading cause of dementia. Although the amyloid-β (Aβ) peptide is deemed a crucial driver of AD, there are no effective therapeutics available to treat Aβ-caused neurotoxicity. Extracellular vesicles (EVs) are membrane-bound small particles mediating intercellular traffic of nucleic acids, lipids, proteins, and metabolites. Exosomes are a subtype of EVs with a size range of 30-150 nm in diameter. Stem cell-derived EVs are a potential therapeutic for AD, while EVs isolated from normal stem cell cultures generally have a low yield. Here, we studied the EVs secreted by the rat neural stem cells in the presence of heat shock (HS) stimulus. Nanoparticle tracking analysis confirmed that HS-derived EVs exhibit significantly higher concentration and larger diameter in comparison to the non-heat shock (NHS)-derived EVs. Mass spectrometric studies of EV proteins revealed that HS-derived EVs contained fewer diverse proteins than NHS-derived exosomes. GO enrichment analysis of the proteins suggested that the top two biological functions of the proteins in HS-derived EVs are involved in the negative regulation of apoptotic process and positive modulation of DNA repair. Importantly, the therapeutic efficacy of the NHS- and HS-derived EVs were tested in a cell culture model of AD: HS-derived EVs exhibited greater neuroprotection against not only oxidative stress but also amyloid-β (Aβ) induced neurotoxicity compared to NHS-derived EVs. Moreover, HS-derived EVs were also able to dramatically attenuate Aβ-induced apoptosis and oxidative stress. These data indicate that in response to HS, neural stem cells increase EV production and alter EV morphology and cargo to confer better neuroprotection against oxidative stress and Aβ-caused neurotoxicity, suggesting that HS-induced EVs from neural stem cells can be a therapeutic agent for AD and possibly other neurological disorders.
    Keywords:  Alzheimer’s disease; Amyloid-β; Exosome; Extracellular vesicle; Heat shock; Neural stem cell; Therapy
    DOI:  https://doi.org/10.1007/s12035-022-03055-3
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