bims-proarb 2022-01-30 papers

bims-proarb

Biomed News

on Proteostasis in aging and regenerative biology

Issue of 2022–01–30
nineteen papers selected by
Rich Giadone, Harvard University

Differential roles for DNAJ isoforms in HTT-polyQ and FUS aggregation modulation revealed by chaperone screens.
Endoplasmic Reticulum Stress-Associated Neuronal Death and Innate Immune Response in Neurological Diseases.
Molecular Investigation of the Unfolded Protein Response in Select Human Tauopathies.
Protein degradation-associated mechanisms that are affected in Alzheimer´s disease.
New Inroads Into Our Understanding of the Tauopathies, Alzheimer's Disease, and the Contribution of Altered Protein Conformation to Human Neurological Disease.
The co-chaperone BAG3: Orchestrator of the cellular task force in response to stress.
Abeta Peptides Disrupt the Barrier Integrity and Glucose Metabolism of Human Induced Pluripotent Stem Cell-Derived Brain Microvascular Endothelial Cells.
Bi-Directional Relationship Between Autophagy and Inflammasomes in Neurodegenerative Disorders.
AKT1 mediates multiple phosphorylation events that functionally promote HSF1 activation.
Ubiquitin ligases: guardians of mammalian development.
Disrupting the balance of protein quality control protein UBQLN2 accelerates tau proteinopathy.
Matrine alleviates spatial learning and memory impairment in diabetic mice by inhibiting endoplasmic reticulum stress and through modulation of PK2/PKRs pathway.
The endoplasmic reticulum chaperone BiP is a closure-accelerating cochaperone of Grp94.
Long noncoding RNA and phase separation in cellular stress response.
A single-cell atlas of the normal and malformed human brain vasculature.
Mendelian randomization analyses implicate biogenesis of translation machinery in human aging.
Age-dependent aggregation of α-synuclein in the nervous system of gut-brain axis is associated with caspase-1 activation.
Influence of Chaperones on Amyloid Formation of Аβ Peptide.
A novel yeast model detects Nrf2 and Keap1 interactions with Hsp90.

Nat Commun. 2022 Jan 26. 13(1): 516

Differential roles for DNAJ isoforms in HTT-polyQ and FUS aggregation modulation revealed by chaperone screens.

Kinneret Rozales, Amal Younis, Naseeb Saida, Anatoly Meller, Hodaya Goldman, Lior Kellerman, Ronit Heinrich, Shai Berlin, Reut Shalgi.

Protein aggregation is a hallmark of neurodegeneration. Here, we find that Huntington's disease-related HTT-polyQ aggregation induces a cellular proteotoxic stress response, while ALS-related mutant FUS (mutFUS) aggregation leads to deteriorated proteostasis. Further exploring chaperone function as potential modifiers of pathological aggregation in these contexts, we reveal divergent effects of naturally-occurring chaperone isoforms on different aggregate types. We identify a complex of the full-length (FL) DNAJB14 and DNAJB12, that substantially protects from mutFUS aggregation, in an HSP70-dependent manner. Their naturally-occurring short isoforms, however, do not form a complex, and lose their ability to preclude mutFUS aggregation. In contrast, DNAJB12-short alleviates, while DNAJB12-FL aggravates, HTT-polyQ aggregation. DNAJB14-FL expression increases the mobility of mutFUS aggregates, and restores the deteriorated proteostasis in mutFUS aggregate-containing cells and primary neurons. Our results highlight a maladaptive cellular response to pathological aggregation, and reveal a layer of chaperone network complexity conferred by DNAJ isoforms, in regulation of different aggregate types.

DOI: https://doi.org/10.1038/s41467-022-27982-w
Front Immunol. 2021 ;12 794580

Endoplasmic Reticulum Stress-Associated Neuronal Death and Innate Immune Response in Neurological Diseases.

Mingming Shi, Yan Chai, Jianning Zhang, Xin Chen.

  Neuronal death and inflammatory response are two common pathological hallmarks of acute central nervous system injury and chronic degenerative disorders, both of which are closely related to cognitive and motor dysfunction associated with various neurological diseases. Neurological diseases are highly heterogeneous; however, they share a common pathogenesis, that is, the aberrant accumulation of misfolded/unfolded proteins within the endoplasmic reticulum (ER). Fortunately, the cell has intrinsic quality control mechanisms to maintain the proteostasis network, such as chaperone-mediated folding and ER-associated degradation. However, when these control mechanisms fail, misfolded/unfolded proteins accumulate in the ER lumen and contribute to ER stress. ER stress has been implicated in nearly all neurological diseases. ER stress initiates the unfolded protein response to restore proteostasis, and if the damage is irreversible, it elicits intracellular cascades of death and inflammation. With the growing appreciation of a functional association between ER stress and neurological diseases and with the improved understanding of the multiple underlying molecular mechanisms, pharmacological and genetic targeting of ER stress are beginning to emerge as therapeutic approaches for neurological diseases.

Keywords:  endoplasmic reticulum stress; inflammatory response; neurological diseases; neuronal death; proteostasis; unfolded protein response

DOI:  https://doi.org/10.3389/fimmu.2021.794580
J Alzheimers Dis Rep. 2021 ;5(1): 855-869

Molecular Investigation of the Unfolded Protein Response in Select Human Tauopathies.

Aleksandra P Pitera, Iain J Hartnell, Lucy Scullard, Kirsten L Williamson, Delphine Boche, Vincent O'Connor, Katrin Deinhardt.

   Background: Tauopathies are a group of neurodegenerative diseases associated with the accumulation of misfolded tau protein. The mechanisms underpinning tau-dependent proteinopathy remain to be elucidated. A protein quality control pathway within the endoplasmic reticulum, the unfolded protein response (UPR), has been suggested as a possible pathway modulating cellular responses in a range of neurodegenerative diseases, including those associated with misfolded cytosolic tau.
Objective: In this study we investigated three different clinically defined tauopathies to establish whether these diseases are accompanied by the activation of UPR.
Methods: We used PCR and western blotting to probe for the modulation of several reliable UPR markers in mRNA and proteins extracted from three distinct tauopathies: 20 brain samples from Alzheimer's disease patients, 11 from Pick's disease, and 10 from progressive supranuclear palsy. In each disease samples from these patients were compared with equal numbers of age-matched non-demented controls.
Results: Our investigation showed that different markers of UPR are not changed at the late stage of any of the human tauopathies investigated. Interestingly, UPR signatures were often observed in non-demented controls.
Conclusion: These data from late-stage human cortical tissue report an activation of UPR markers within the aged brain across all cohorts investigated and further support the emerging evidence that the accumulation of misfolded cytosolic tau does not drive a disease-associated activation of UPR.

Keywords:  Alzheimer’s disease; BiP; Pick’s disease; XBP-1; endoplasmic reticulum; progressive supranuclear palsy; tau

DOI:  https://doi.org/10.3233/ADR-210050
Mol Cell Biochem. 2022 Jan 27.

Protein degradation-associated mechanisms that are affected in Alzheimer´s disease.

Angeles C Tecalco-Cruz, José Pedraza-Chaverri, Alfredo Briones-Herrera, Eduardo Cruz-Ramos, Lilia López-Canovas, Jesús Zepeda-Cervantes.

  Alzheimer's disease (AD) is the most common type of dementia associated with age-related neurodegeneration. Alteration of several molecular mechanisms has been correlated with the progression of AD. In recent years, dysregulation of proteostasis-associated pathways has emerged as a potential risk factor for neurodegenerative diseases. This review investigated the ubiquitin-proteasome system, lysosome-associated degradation, endoplasmic-reticulum-associated degradation, and the formation of advanced glycation end products. These pathways involved in proteostasis have been reported to be altered in AD, suggesting that their study may be critical for identifying new biomarkers and target molecules for AD.

Keywords:  Alzheimer; Autophagy; Protein degradation; The ubiquitin–proteasome system

DOI:  https://doi.org/10.1007/s11010-021-04334-8
Front Neurosci. 2021 ;15 817983

New Inroads Into Our Understanding of the Tauopathies, Alzheimer's Disease, and the Contribution of Altered Protein Conformation to Human Neurological Disease.

Walter J Lukiw.



Keywords:  Alzheimer's disease (AD); neurodegeneration; prion disease (PrD); protein folding; tauopathies

DOI:  https://doi.org/10.3389/fnins.2021.817983
J Cell Biochem. 2022 Jan;123(1): 3

The co-chaperone BAG3: Orchestrator of the cellular task force in response to stress.

Alessandra Rosati, Maria Caterina Turco.



Keywords:  BAG3; co-chaperone; stress response

DOI:  https://doi.org/10.1002/jcb.30212
Neurotoxicology. 2022 Jan 19. pii: S0161-813X(22)00015-8. [Epub ahead of print]

Abeta Peptides Disrupt the Barrier Integrity and Glucose Metabolism of Human Induced Pluripotent Stem Cell-Derived Brain Microvascular Endothelial Cells.

Snehal Raut, Ronak Patel, Iqra Pervaiz, Abraham J Al-Ahmad.

  Amyloid β (Aβ) peptides are key components of Alzheimer's disease and cerebral amyloid angiopathy and have been associated with detrimental effects at the blood-brain barrier (BBB) in vivo. Yet, the cellular and molecular mechanisms by which such peptides exert their effect on the brain vasculature remain unclear. This study aimed to assess the cellular response of induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cells (BMECs) to Aβ peptides. Changes in the barrier function, efflux transporters activity, glucose uptake, and metabolism were assessed in such model. Although iPSC-derived BMECs sustained prolonged exposure (<72 hours) to a high level of Aβ peptides including Aβ42, such cells also suffered from a loss of barrier integrity, coupled with reduced glucose uptake and impaired bioenergetic activity. Taken together, this study shows the ability of iPSC-derived BMECs to reproduce features observed in other models and suggests that Aβ peptides may compromise the BBB via different targets.

Keywords:  Aβ peptides; Blood-brain barrier; amyloid; induced pluripotent stem cells; metabolism

DOI:  https://doi.org/10.1016/j.neuro.2022.01.007
Cell Mol Neurobiol. 2022 Jan 23.

Bi-Directional Relationship Between Autophagy and Inflammasomes in Neurodegenerative Disorders.

Chinmaya Panda, Rajani Kanta Mahapatra.

  The innate immune system, as the first line of cellular defense, triggers a protective response called inflammation when encountered with invading pathogens. Inflammasome is a multi-protein cytosolic signaling complex that induces inflammation and is critical for inflammation-induced pyroptotic cell death. Inflammasome activation has been found associated with neurodegenerative disorders (NDs), inflammatory diseases, and cancer. Autophagy is a crucial intracellular quality control and homeostasis process which removes the dysfunctional organelles, damaged proteins, and pathogens by sequestering the cytosolic components in a double-membrane vesicle, which eventually fuses with lysosome resulting in cargo degradation. Autophagy disruption has been observed in many NDs presented with persistent neuroinflammation and excessive inflammasome activation. An interplay between inflammation activation and the autophagy process has been realized over the last decade. In the case of NDs, autophagy regulates neuroinflammation load and cellular damage either by engulfing the misfolded protein deposits, dysfunctional mitochondria, or the inflammasome complex itself. A healthy two-way regulation between both cellular processes has been realized for cell survival and cell defense during inflammatory conditions. Therefore, clinical interest in the modulation of inflammasome activation by autophagy inducers is rapidly growing. In this review, we discuss the structural basis of inflammasome activation and the mechanistic ideas of the autophagy process in NDs. Along with comments on multiple ways of neuroinflammation regulation by microglial autophagy, we also present a perspective on pharmacological opportunities in this molecular interplay pertaining to NDs.

Keywords:  Alzheimer’s disease; Autophagy; Inflammasome; NLRP3; Neurodegeneration

DOI:  https://doi.org/10.1007/s10571-021-01184-2
FEBS J. 2022 Jan 26.

AKT1 mediates multiple phosphorylation events that functionally promote HSF1 activation.

Wen-Cheng Lu, Ramsey Omari, Haimanti Ray, John Wang, Imade Williams, Curteisha Jacobs, Natasha Hockaden, Matthew L Bochman, Richard L Carpenter.

  The heat stress response activates the transcription factor heat shock factor 1 (HSF1), which subsequently upregulates heat shock proteins to maintain the integrity of the proteome. HSF1 activation requires nuclear localization, trimerization, DNA binding, phosphorylation, and gene transactivation. Phosphorylation at S326 is an important regulator of HSF1 transcriptional activity. Phosphorylation at S326 is mediated by AKT1, mTOR, p38, MEK1, and DYRK2. Here, we observed activation of HSF1 by AKT1 independently of mTOR. AKT2 also phosphorylated S326 of HSF1 but showed weak ability to activate HSF1. Similarly, mTOR, p38, MEK1, and DYRK2 all phosphorylated S326 but AKT1 was the most potent activator. Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230, and T527 in addition to S326 whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326, and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9. Interestingly, T527 as a phosphorylated residue has not been previously shown and sits in the transactivation domain, further implying a role for this site in HSF1 gene transactivation. This study suggests that HSF1 hyperphosphorylation is targeted and these specific residues have direct function in regulating HSF1 transcriptional activity.

Keywords:  AKT1; HSF1; heat shock; phosphorylation

DOI:  https://doi.org/10.1111/febs.16375
Nat Rev Mol Cell Biol. 2022 Jan 25.

Ubiquitin ligases: guardians of mammalian development.

David A Cruz Walma, Zhuoyao Chen, Alex N Bullock, Kenneth M Yamada.

Mammalian development demands precision. Millions of molecules must be properly located in temporal order, and their function regulated, to orchestrate important steps in cell cycle progression, apoptosis, migration and differentiation, to shape developing embryos. Ubiquitin and its associated enzymes act as cellular guardians to ensure precise spatio-temporal control of key molecules during each of these important cellular processes. Loss of precision results in numerous examples of embryological disorders or even cancer. This Review discusses the crucial roles of E3 ubiquitin ligases during key steps of early mammalian development and their roles in human disease, and considers how new methods to manipulate and exploit the ubiquitin regulatory machinery - for example, the development of molecular glues and PROTACs - might facilitate clinical therapy.

DOI: https://doi.org/10.1038/s41580-021-00448-5
J Neurosci. 2022 Jan 06. pii: JN-RM-1116-21. [Epub ahead of print]

Disrupting the balance of protein quality control protein UBQLN2 accelerates tau proteinopathy.

Julia E Gerson, Stephanie Sandoval-Pistorius, Jacqueline P Welday, Aleija Rodriguez, Jordan D Gregory, Nyjerus Liggans, Kylie Schache, Xingli Li, Hanna Trzeciakiewicz, Sami Barmada, Lisa M Sharkey, Henry L Paulson.

Tau protein accumulation drives toxicity in several neurodegenerative disorders. To better understand the pathways regulating tau homeostasis in disease, we investigated the role of ubiquilins (UBQLNs)-a class of proteins linked to ubiquitin-mediated protein quality control (PQC) and various neurodegenerative diseases-in regulating tau. Cell-based assays identified UBQLN2 as the primary brain-expressed UBQLN to regulate tau. UBQLN2 efficiently lowered wild-type tau levels irrespective of aggregation, suggesting that UBQLN2 interacts with and regulates tau protein under normal conditions or early in disease. Moreover, UBQLN2 itself proved to be prone to accumulation as insoluble protein in male and female tau transgenic mice and the human tauopathy progressive supranuclear palsy. Genetic manipulation of UBQLN2 in a tauopathy mouse model demonstrated that a physiological UBQLN2 balance is required for tau homeostasis. UBQLN2 overexpression exacerbated phosphorylated tau pathology and toxicity in mice expressing P301S mutant tau, whereas P301S mice lacking UBQLN2 showed significantly reduced phosphorylated tau. Further studies support the view that an imbalance of UBQLN2 perturbs ubiquitin-dependent PQC and autophagy. We conclude that changes in UBQLN2 levels, whether due to pathogenic mutations or secondary to disease states such as tauopathy, contribute to proteostatic imbalances that exacerbate neurodegeneration.SIGNIFICANCE STATEMENT We defined a role for the protein quality control protein, Ubiquilin-2 (UBQLN2), in age-related neurodegenerative tauopathies. This group of disorders is characterized by the accumulation of tau protein aggregates, which differ when UBQLN2 levels are altered. Given the lack of effective disease-modifying therapies for tauopathies and UBQLN2's function in handling various disease-linked proteins, we explored the role of UBQLN2 in regulating tau. We found that UBQLN2 reduced tau levels in cell models but behaved differently in mouse brain, where it accelerated mutant tau pathology and tau-mediated toxicity. A better understanding of the diverse functions of regulatory proteins like UBQLN2 can elucidate some of the causative factors in neurodegenerative disease and outline new routes to therapeutic intervention.

DOI: https://doi.org/10.1523/JNEUROSCI.1116-21.2021
Neurochem Int. 2022 Jan 21. pii: S0197-0186(22)00014-6. [Epub ahead of print] 105289

Matrine alleviates spatial learning and memory impairment in diabetic mice by inhibiting endoplasmic reticulum stress and through modulation of PK2/PKRs pathway.

Ruyi Zhang, Wenli Liao, Ke Wu, Liangliang Hua, Mengyu Wu, Cairong Li, Fei Cai.

  Clinical and epidemiological studies indicate that diabetic cognitive impairment often occurs in diabetes mellitus patients. Matrine (Mat), an active component of Sophora flavescens Ait root extracts, has widely pharmacological activities including anti-tumor, anti-diabetes, cardioprotective and neuroprotective effects. The present study was designed to elucidate the possibly neuroprotective effects of Mat against diabetic spatial learning and memory impairment caused by high-fat diet and streptozotocin injection in mice. The results showed that Mat treatment significantly ameliorated fasting blood glucose level, impaired glucose tolerance, and lipid metabolism disorder in diabetic mice. In addition, diabetic mice exhibited spatial learning and memory impairment in the Morris water maze test, which could be attenuated by Mat treatment. Moreover, administration of Mat remarkably alleviated histological damage in diabetic hippocampus. Also, further investigations showed that Mat treatment abated endoplasmic reticulum stress induced hippocampal ultra-structure injury as evidenced by increasing the numbers of rough endoplasmic reticulum and mitochondria, as well as down-regulating endoplasmic reticulum stress related protein levels (GRP78, CHOP, ATF6 and Caspase-12). Furthermore, administration of Mat enhanced hippocampal protein expressions of PK2, PKR1 and PKR2, which decreased significantly in diabetic mice. Collectively, these findings suggested that Mat could ameliorate diabetes-induced spatial learning and memory impairment, possibly by alleviating ER stress, and partly through modulation of PK2/PKRs pathway.

Keywords:  Diabetes mellitus; Endoplasmic reticulum; Learning and memory impairment; Matrine; Prokineticin 2

DOI:  https://doi.org/10.1016/j.neuint.2022.105289
Proc Natl Acad Sci U S A. 2022 Feb 01. pii: e2118793119. [Epub ahead of print]119(5):

The endoplasmic reticulum chaperone BiP is a closure-accelerating cochaperone of Grp94.

Bin Huang, Ming Sun, Reyal Hoxie, Judy L M Kotler, Larry J Friedman, Jeff Gelles, Timothy O Street.

  Hsp70 and Hsp90 chaperones provide protein quality control to the cytoplasm, endoplasmic reticulum (ER), and mitochondria. Hsp90 activity is often enhanced by cochaperones that drive conformational changes needed for ATP-dependent closure and capture of client proteins. Hsp90 activity is also enhanced when working with Hsp70, but, in this case, the underlying mechanistic explanation is poorly understood. Here we examine the ER-specific Hsp70/Hsp90 paralogs (BiP/Grp94) and discover that BiP itself acts as a cochaperone that accelerates Grp94 closure. The BiP nucleotide binding domain, which interacts with the Grp94 middle domain, is responsible for Grp94 closure acceleration. A client protein initiates a coordinated progression of steps for the BiP/Grp94 system, in which client binding to BiP causes a conformational change that enables BiP to bind to Grp94 and accelerate its ATP-dependent closure. Single-molecule fluorescence resonance energy transfer measurements show that BiP accelerates Grp94 closure by stabilizing a high-energy conformational intermediate that otherwise acts as an energetic barrier to closure. These findings provide an explanation for enhanced activity of BiP and Grp94 when working as a pair, and demonstrate the importance of a high-energy conformational state in controlling the timing of the Grp94 conformational cycle. Given the high conservation of the Hsp70/Hsp90 system, other Hsp70s may also serve dual roles as both chaperones and closure-accelerating cochaperones to their Hsp90 counterparts.

Keywords:  BiP; Grp94; chaperone; cochaperone

DOI:  https://doi.org/10.1073/pnas.2118793119
J Biochem. 2022 Jan 26. pii: mvab156. [Epub ahead of print]

Long noncoding RNA and phase separation in cellular stress response.

Rena Onoguchi-Mizutani, Nobuyoshi Akimitsu.

  Stress response is important for sensing and adapting to environmental changes. Recently, RNA-protein condensates, which are a type of membrane-less organelle formed by liquid-liquid phase separation, have been proposed to regulate the stress response. Because RNA-protein condensates are formed through interactions between positively charged proteins and negatively charged RNAs, the ratio of proteins to RNAs is critical for phase-separated condensate formation. In particular, long noncoding RNAs (lncRNAs) can efficiently nucleate phase-separated RNA-protein condensates because of their secondary structure and long length. Therefore, increased attention has been paid to lncRNAs because of their potential role as a regulator of biological condensates by phase separation under stress response. In this review, we summarize the current research on the involvement of lncRNAs in the formation of RNA-protein condensates under stress response. We also demonstrate that lncRNA-driven phase separation provides a useful basis to understanding the response to several kinds of cellular stresses.

Keywords:  Long noncoding RNA; RNA-binding protein; RNA-protein condensate; phase separation; stress response

DOI:  https://doi.org/10.1093/jb/mvab156
Science. 2022 Jan 27. eabi7377

A single-cell atlas of the normal and malformed human brain vasculature.

Ethan A Winkler, Chang N Kim, Jayden M Ross, Joseph H Garcia, Eugene Gil, Irene Oh, Lindsay Q Chen, David Wu, Joshua S Catapano, Kunal Raygor, Kazim Narsinh, Helen Kim, Shantel Weinsheimer, Daniel L Cooke, Brian P Walcott, Michael T Lawton, Nalin Gupta, Berislav V Zlokovic, Edward F Chang, Adib A Abla, Daniel A Lim, Tomasz J Nowakowski.

Cerebrovascular diseases are a leading cause of death and neurologic disability. Further understanding of disease mechanisms and therapeutic strategies requires a deeper knowledge of cerebrovascular cells in humans. We profiled transcriptomes of 181,388 cells to define a cell atlas of the adult human cerebrovasculature, including endothelial cell molecular signatures with arteriovenous segmentation and expanded perivascular cell diversity. By leveraging this reference, we investigated cellular and molecular perturbations in brain arteriovenous malformations, a leading cause of stroke in young people, and identified pathologic endothelial transformations with abnormal vascular patterning and the ontology of vascularly derived inflammation. Here, we illustrate the interplay between vascular and immune cells that contributes to brain hemorrhage and catalog opportunities for targeting angiogenic and inflammatory programs in vascular malformations.

DOI: https://doi.org/10.1126/science.abi7377
Genome Res. 2022 Jan 25.

Mendelian randomization analyses implicate biogenesis of translation machinery in human aging.

Sara Javidnia, Stephen Cranwell, Stefanie H Mueller, Colin Selman, Jennifer M A Tullet, Karoline Kuchenbaecker, Nazif Alic.

Reduced provision of protein translation machinery promotes healthy aging in a number of animal models. In humans, however, inborn impairments in translation machinery are a known cause of several developmental disorders, collectively termed ribosomopathies. Here, we use casual inference approaches in genetic epidemiology to investigate whether adult, tissue-specific biogenesis of translation machinery drives human aging. We assess naturally occurring variation in the expression of genes encoding subunits specific to the two RNA polymerases (Pols) that transcribe ribosomal and transfer RNAs, namely Pol I and III, and the variation in expression of ribosomal protein (RP) genes, using Mendelian randomization. We find each causally associated with human longevity (β = -0.15 ± 0.047, P = 9.6 × 10-4, q = 0.015; β = -0.13 ± 0.040, P = 1.4 × 10-3, q = 0.023; β = -0.048 ± 0.016, P = 3.5 × 10-3, q = 0.056, respectively), and this does not appear to be mediated by altered susceptibility to a single disease. We find that reduced expression of Pol III, RPs, or Pol I promotes longevity from different organs, namely visceral adipose, liver, and skeletal muscle, echoing the tissue specificity of ribosomopathies. Our study shows the utility of leveraging genetic variation in expression to elucidate how essential cellular processes impact human aging. The findings extend the evolutionary conservation of protein synthesis as a critical process that drives animal aging to include humans.

DOI: https://doi.org/10.1101/gr.275636.121
Metab Brain Dis. 2022 Jan 28.

Age-dependent aggregation of α-synuclein in the nervous system of gut-brain axis is associated with caspase-1 activation.

Qi Hu, Mei Hong, Mengyang Huang, Quan Gong, Xiaofan Zhang, Vladimir N Uversky, Francisco Pan-Montojo, Teng Huang, Honglian Zhou, Suiqiang Zhu.

  α-Synuclein (α-Syn) plays a key role in the development of Parkinson' desease (PD). As aging is acknowledged to be the greatest risk factor for PD, here we investigated α-Syn expression in the ileum, thoracic spinal cord, and midbrain of young (1-month-old), middle-aged (6-, 12-month-old) to old (18-month-old) mice. We demonstrated that both the levels of α-Syn monomers, oligomers and ratios of oligomers to monomers were increased with aging in the ileum, thoracic spinal cord, and midbrain. Whereas, the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis, was decreased with aging in the midbrain. We failed to find corresponding α-Syn mRNA increase with aging. However, we found an increased expression of caspase-1 in the ileum, thoracic spinal cord, and midbrain. A specific caspase-1 inhibitor VX765 significantly reduced levels of both the α-Syn monomers and oligomers triggered by the rotenone in vitro. Taken together, the increase in α-Syn aggregation with aging might not occur first in the gut, but simultaneously in the nervous system of gut-brain axis. The mechanism of the age-dependent aggregation of α-Syn in nervous system is likely triggered by the aging-related caspase-1 activation.

Keywords:  Aging; Caspase-1; Parkinson’ desease; Rotenone; α-Synuclein

DOI:  https://doi.org/10.1007/s11011-022-00917-6
Curr Protein Pept Sci. 2022 Jan 27.

Influence of Chaperones on Amyloid Formation of Аβ Peptide.

O V Galzitskaya, O M Selivanova, U F Dzhus, V V Marchenkov, M Yu Suvorina, A K Surin.

   BACKGROUND: An extensive study of the folding and stability of proteins and their complexes has revealed a number of problems and questions that need to be answered. One of them is the effect of chaperones on the process of fibrillation of various proteins and peptides.
METHODS: We studied the effect of molecular chaperones, such as GroEL and α-crystallin, on the fibrillogenesis of the Aβ(1-42) peptide.
RESULT: Recombinant GroEL and Aβ(1-42) were isolated and purified. It was shown that the assembly of GroEL occurs without the addition of magnesium and potassium ions, as is commonly believed. According to the electron microscopy results, GroEL insignificantly affects the fibrillogenesis of the Aβ(1-42) peptide, while α-crystallin prevents the elongation of the Aβ(1-42) peptide fibrils.
CONCLUSION: The data obtained will help us understand the process of amyloid formation and the effect of various components on it.

Keywords:  aggregation; chaperones; electron microscopy; fibrils; mass spectrometry; nucleus

DOI:  https://doi.org/10.2174/1389203723666220127152545
Dis Model Mech. 2022 Jan 28. pii: dmm.049258. [Epub ahead of print]

A novel yeast model detects Nrf2 and Keap1 interactions with Hsp90.

Vy Ngo, Anne Brickenden, Hansen Liu, Cynthia Yeung, Wing-Yiu Choy, Martin L Duennwald.

  Nrf2 is the master transcriptional regulator of cellular responses against oxidative stress. It is chiefly regulated by Keap1, a substrate adaptor protein that mediates Nrf2 degradation. Nrf2 activity is also influenced by many other protein interactions that provide Keap1-independent regulation. To study Nrf2 regulation, we establish and characterize yeast models expressing human Nrf2, Keap1, and other proteins that interact with and regulate Nrf2. Yeast models have been well-established as powerful tools to study protein function and genetic and physical protein-protein interactions. In this work, we recapitulate previously described Nrf2 interactions in yeast and discover that Nrf2 interacts with the molecular chaperone Hsp90. Our work establishes yeast as a useful tool to study Nrf2 interactions and provides novel insight into the crosstalk between the antioxidant response and the heat shock response.

Keywords:  Hsp90; Keap1; Molecular chaperones; Nrf2; Protein interactions; Yeast model

DOI:  https://doi.org/10.1242/dmm.049258