bims-proarb 2021-12-12 papers

bims-proarb

Biomed News

on Proteostasis in aging and regenerative biology

Issue of 2021–12–12
twenty-one papers selected by
Rich Giadone, Harvard University

Chaperone networks are shaped by cellular differentiation and identity.
Heat Shock Factor 1 Directly Regulates Postsynaptic Scaffolding PSD-95 in Aging and Huntington's Disease and Influences Striatal Synaptic Density.
Oxidative distress in aging and age-related diseases: Spatiotemporal dysregulation of protein oxidation and degradation.
Molecular Strategies to Target Protein Aggregation in Huntington's Disease.
The Interplay of the Unfolded Protein Response in Neurodegenerative Diseases: A Therapeutic Role of Curcumin.
A permissive epigenetic landscape facilitates distinct transcriptional signatures of activating transcription factor 6 in the liver.
Serum from Older Adults Increases Apoptosis and Molecular Aging Markers in Human Hippocampal Progenitor Cells.
Adult Neural Stem Cell Migration Is Impaired in a Mouse Model of Alzheimer's Disease.
Truncation-Driven Lateral Association of α-Synuclein Hinders Amyloid Clearance by the Hsp70-Based Disaggregase.
Probing Interplays between Human XBP1u Translational Arrest Peptide and 80S Ribosome.
Serum supplementation during bovine embryo culture affects their development and proliferation through macroautophagy and endoplasmic reticulum stress regulation.
Neuronal Deposition of Amyloid-β Oligomers and Hyperphosphorylated Tau Is Closely Connected with Cognitive Dysfunction in Aged Dogs.
Expression and proteolytic processing of the amyloid precursor protein is unaffected by the expression of the three human apolipoprotein E alleles in the brains of mice.
Role of Autophagy in Cardiovascular Disease and Aging.
Reciprocal regulation of chaperone-mediated autophagy and the circadian clock.
Mitophagy in aging and longevity.
Aggregates of TDP-43 protein spiral into view.
Sex Differences in Behavior and Molecular Pathology in the 5XFAD Model.
Class-specific interactions between Sis1 J-domain protein and Hsp70 chaperone potentiate disaggregation of misfolded proteins.
High Fat Diet Mediates Amyloid-β Cleaving Enzyme 1 Phosphorylation and SUMOylation, Enhancing Cognitive Impairment in APP/PS1 Mice.
Comparing anti-aging hallmark activities of Metformin and Nano-PSO in a mouse model of genetic Creutzfeldt-Jakob Disease.

Trends Cell Biol. 2021 Dec 01. pii: S0962-8924(21)00227-0. [Epub ahead of print]

Chaperone networks are shaped by cellular differentiation and identity.

Khairun Nisaa, Anat Ben-Zvi.

  Chaperone expression is developmentally regulated, establishing tissue-specific networks. However, the molecular basis underlying this specificity is mainly unknown. Recent evidence suggests that chaperone network rewiring is mediated, in part, by differentiation transcription factors to fit the proteome folding demands, with implications for the tissue-specific manifestation of protein misfolding diseases.

Keywords:  chaperone; differentiation; proteostasis; stress

DOI:  https://doi.org/10.1016/j.tcb.2021.11.001
Int J Mol Sci. 2021 Dec 04. pii: 13113. [Epub ahead of print]22(23):

Heat Shock Factor 1 Directly Regulates Postsynaptic Scaffolding PSD-95 in Aging and Huntington's Disease and Influences Striatal Synaptic Density.

Nicole Zarate, Taylor A Intihar, Dahyun Yu, Jacob Sawyer, Wei Tsai, Maha Syed, Luke Carlson, Rocio Gomez-Pastor.

  PSD-95 (Dlg4) is an ionotropic glutamate receptor scaffolding protein essential in synapse stability and neurotransmission. PSD-95 levels are reduced during aging and in neurodegenerative diseases like Huntington's disease (HD), and it is believed to contribute to synaptic dysfunction and behavioral deficits. However, the mechanism responsible for PSD-95 dysregulation under these conditions is unknown. The Heat Shock transcription Factor 1 (HSF1), canonically known for its role in protein homeostasis, is also depleted in both aging and HD. Synaptic protein levels, including PSD-95, are influenced by alterations in HSF1 levels and activity, but the direct regulatory relationship between PSD-95 and HSF1 has yet to be determined. Here, we showed that HSF1 chronic or acute reduction in cell lines and mice decreased PSD-95 expression. Furthermore, Hsf1(+/-) mice had reduced PSD-95 synaptic puncta that paralleled a loss in thalamo-striatal excitatory synapses, an important circuit disrupted early in HD. We demonstrated that HSF1 binds to regulatory elements present in the PSD-95 gene and directly regulates PSD-95 expression. HSF1 DNA-binding on the PSD-95 gene was disrupted in an age-dependent manner in WT mice and worsened in HD cells and mice, leading to reduced PSD-95 levels. These results demonstrate a direct role of HSF1 in synaptic gene regulation that has important implications in synapse maintenance in basal and pathological conditions.

Keywords:  HSF1; Huntington’s disease; PSD-95; aging

DOI:  https://doi.org/10.3390/ijms222313113
Biochimie. 2021 Dec 07. pii: S0300-9084(21)00273-X. [Epub ahead of print]

Oxidative distress in aging and age-related diseases: Spatiotemporal dysregulation of protein oxidation and degradation.

Sergey Zavadskiy, Susanna Sologova, Nurbubu Moldogazieva.

  The concept of oxidative distress had arisen from the assessment of cellular response to high concentrations of reactive species that result from an imbalance between oxidants and antioxidants and cause biomolecular damage. The intracellular distribution and flux of reactive species dramatically change in time and space contributing to the remodeling of the redox landscape and sensitivity of protein residues to oxidants. Here, we hypothesize that compromised spatiotemporal control of generation, conversions, and removal of reactive species underlies protein damage and dysfunction of protein degradation machineries. This leads to the accumulation of oxidatively damaged proteins resulted in an age-dependent decline in the organismal adaptability to oxidative stress. We highlight recent data obtained with the use of various cell cultures, animal models, and patients on irreversible and non-repairable oxidation of key redox-sensitive residues. Multiple reaction products include peptidyl hydroperoxides, alcohols, carbonyls, and carbamoyl moieties as well as Tyr-Tyr, Trp-Tyr, Trp-Trp, Tyr-Cys, His-Lys, His-Arg, and Tyr-Lys cross-links. These lead to protein fragmentation, misfolding, covalent cross-linking, oligomerization, aggregation, and ultimately, causing impaired protein function and turnover. 20S proteasome and autophagy-lysosome pathways are two major types of machinery for the degradation and elimination of oxidatively damaged proteins. Spatiotemporal dysregulation of these pathways under oxidative distress conditions is implicated in aging and age-related disorders such as neurodegenerative and cardiovascular diseases and diabetes. Future investigations in this field allow the discovery of new drugs to target components of dysregulated cell signaling and protein degradation machinery to combat aging and age-related chronic diseases.

Keywords:  Aging and age-related diseases; Autophagy-lysosome; Oxidative stress; Proteasome; Protein oxidation and damage; Spatiotemporal regulation

DOI:  https://doi.org/10.1016/j.biochi.2021.12.002
Front Mol Biosci. 2021 ;8 769184

Molecular Strategies to Target Protein Aggregation in Huntington's Disease.

Olga D Jarosińska, Stefan G D Rüdiger.

  Huntington's disease (HD) is a neurodegenerative disorder caused by the aggregation of the mutant huntingtin (mHTT) protein in nerve cells. mHTT self-aggregates to form soluble oligomers and insoluble fibrils, which interfere in a number of key cellular functions. This leads to cell quiescence and ultimately cell death. There are currently still no treatments available for HD, but approaches targeting the HTT levels offer systematic, mechanism-driven routes towards curing HD and other neurodegenerative diseases. This review summarizes the current state of knowledge of the mRNA targeting approaches such as antisense oligonucleotides and RNAi system; and the novel methods targeting mHTT and aggregates for degradation via the ubiquitin proteasome or the autophagy-lysosomal systems. These methods include the proteolysis-targeting chimera, Trim-Away, autophagosome-tethering compound, autophagy-targeting chimera, lysosome-targeting chimera and approach targeting mHTT for chaperone-mediated autophagy. These molecular strategies provide a knowledge-based approach to target HD and other neurodegenerative diseases at the origin.

Keywords:  aggregation; huntingtin (HTT); huntington’s disease; mRNA degradation; protein degradation; protein fibrils; protein quality control; proteostasis

DOI:  https://doi.org/10.3389/fmolb.2021.769184
Front Aging Neurosci. 2021 ;13 767493

The Interplay of the Unfolded Protein Response in Neurodegenerative Diseases: A Therapeutic Role of Curcumin.

Sitabja Mukherjee, Awdhesh Kumar Mishra, G D Ghouse Peer, Sali Abubaker Bagabir, Shafiul Haque, Ramendra Pati Pandey, V Samuel Raj, Neeraj Jain, Atul Pandey, Santosh Kumar Kar.

  Abnormal accumulation of misfolded proteins in the endoplasmic reticulum and their aggregation causes inflammation and endoplasmic reticulum stress. This promotes accumulation of toxic proteins in the body tissues especially brain leading to manifestation of neurodegenerative diseases. The studies suggest that deregulation of proteostasis, particularly aberrant unfolded protein response (UPR) signaling, may be a common morbific process in the development of neurodegeneration. Curcumin, the mixture of low molecular weight polyphenolic compounds from turmeric, Curcuma longa has shown promising response to prevents many diseases including current global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and neurodegenerative disorders. The UPR which correlates positively with neurodegenerative disorders were found affected by curcumin. In this review, we examine the evidence from many model systems illustrating how curcumin interacts with UPR and slows down the development of various neurodegenerative disorders (ND), e.g., Alzheimer's and Parkinson's diseases. The recent global increase in ND patients indicates that researchers and practitioners will need to develop a new pharmacological drug or treatment to manage and cure these neurodegenerative diseases.

Keywords:  Alzheimer’s disease; ER stress; Parkinson’s disease; ROS—reactive oxygen species; cell death; curcumin; neurodegenaration; unfolded protein response

DOI:  https://doi.org/10.3389/fnagi.2021.767493
Genomics. 2021 Dec 01. pii: S0888-7543(21)00416-X. [Epub ahead of print]

A permissive epigenetic landscape facilitates distinct transcriptional signatures of activating transcription factor 6 in the liver.

Anjana Ramdas Nair, Priyanka Lakhiani, Chi Zhang, Filippo Macchi, Kirsten C Sadler.

  Restoring homeostasis following proteostatic stress hinges on a stress-specific transcriptional signature. How these signatures are regulated is unknown. We use functional genomics to uncover how activating transcription factor 6 (ATF6), a central factor in the unfolded protein response, regulates its target genes in response to toxicant induced and physiological stress in the liver. We identified 652 conserved putative ATF6 targets (CPATs), which functioned in metabolism, development and proteostasis. Strikingly, Atf6 activation in the zebrafish liver by transgenic nAtf6 overexpression, ethanol and arsenic exposure resulted in a distinct CPAT signature for each; with only 34 CPATs differentially expressed in all conditions. In contrast, during liver regeneration in mice resulted in a dynamic differential expression pattern of 53% of CPATs. These CPATs were distinguished by residing in open chromatin, H3K4me3 occupancy and the absence of H3K27me3 on their promoters. This suggests that a permissive epigenetic landscape allows stress-specific Atf6 target gene expression.

Keywords:  ATF6; Chromatin; Epigenome; Liver; Unfolded Protein response

DOI:  https://doi.org/10.1016/j.ygeno.2021.11.034
Aging Dis. 2021 Dec;12(8): 2151-2172

Serum from Older Adults Increases Apoptosis and Molecular Aging Markers in Human Hippocampal Progenitor Cells.

Chiara de Lucia, Tytus Murphy, Aleksandra Maruszak, Paul Wright, Timothy R Powell, Naomi Hartopp, Simone de Jong, Michael J O'Sullivan, Gerome Breen, Jack Price, Simon Lovestone, Sandrine Thuret.

  Age-related alteration in neural stem cell function is linked to neurodegenerative conditions and cognitive decline. In rodents, this can be reversed by exposure to a young systemic milieu and conversely, the old milieu can inhibit stem cell function in young rodents. In this study, we investigated the in vitro effect of the human systemic milieu on human hippocampal progenitor cells (HPCs) using human serum from early adulthood, mid-life and older age. We showed that neuroblast number following serum treatment is predictive of larger dentate gyrus, CA3, CA4 and whole hippocampus volumes and that allogeneic human serum from asymptomatic older individuals induced a two-fold increase in apoptotic cell death of HPCs compared with serum from young adults. General linear models revealed that variability in markers of proliferation and differentiation was partly attributable to use of antihypertensive medication and very mild cognitive decline among older subjects. Finally, using an endophenotype approach and whole-genome expression arrays, we showed upregulation of established and novel ageing molecular hallmarks in response to old serum. Serum from older subjects induced a wide range of cellular and molecular phenotypes, likely reflecting a lifetime of environmental exposures. Our findings support a role for the systemic enviroment in neural stem cell maintenance and are in line with others highlighting a distinction between neurobiological and chronological ageing. Finally, the herein described serum assay can be used by future studies to further analyse the effect of environmental exposures as well as to determine the role of the systemic environment in health and disease.

Keywords:  ageing; cell death; hippocampus; neural stem cells; neurogenesis; systemic environment

DOI:  https://doi.org/10.14336/AD.2021.0409
Mol Neurobiol. 2021 Dec 11.

Adult Neural Stem Cell Migration Is Impaired in a Mouse Model of Alzheimer's Disease.

Daniel Esteve, María Micaela Molina-Navarro, Esther Giraldo, Noelia Martínez-Varea, Mari-Carmen Blanco-Gandia, Marta Rodríguez-Arias, José Manuel García-Verdugo, José Viña, Ana Lloret.

  Neurogenesis in the adult brain takes place in two neurogenic niches: the ventricular-subventricular zone (V-SVZ) and the subgranular zone. After differentiation, neural precursor cells (neuroblasts) have to move to an adequate position, a process known as neuronal migration. Some studies show that in Alzheimer's disease, the adult neurogenesis is impaired. Our main aim was to investigate some proteins involved both in the physiopathology of Alzheimer's disease and in the neuronal migration process using the APP/PS1 Alzheimer's mouse model. Progenitor migrating cells are accumulated in the V-SVZ of the APP/PS1 mice. Furthermore, we find an increase of Cdh1 levels and a decrease of Cdk5/p35 and cyclin B1, indicating that these cells have an alteration of the cell cycle, which triggers a senescence state. We find less cells in the rostral migratory stream and less mature neurons in the olfactory bulbs from APP/PS1 mice, leading to an impaired odour discriminatory ability compared with WT mice. Alzheimer's disease mice present a deficit in cell migration from V-SVZ due to a senescent phenotype. Therefore, these results can contribute to a new approach of Alzheimer's based on senolytic compounds or pro-neurogenic factors.

Keywords:  Beta-amyloid toxicity; Neurogenesis; Olfaction; Senescence; Subventricular zone

DOI:  https://doi.org/10.1007/s12035-021-02620-6
Int J Mol Sci. 2021 Nov 30. pii: 12983. [Epub ahead of print]22(23):

Truncation-Driven Lateral Association of α-Synuclein Hinders Amyloid Clearance by the Hsp70-Based Disaggregase.

Aitor Franco, Jorge Cuéllar, José Ángel Fernández-Higuero, Igor de la Arada, Natalia Orozco, José M Valpuesta, Adelina Prado, Arturo Muga.

  The aggregation of α-synuclein is the hallmark of a collective of neurodegenerative disorders known as synucleinopathies. The tendency to aggregate of this protein, the toxicity of its aggregation intermediates and the ability of the cellular protein quality control system to clear these intermediates seems to be regulated, among other factors, by post-translational modifications (PTMs). Among these modifications, we consider herein proteolysis at both the N- and C-terminal regions of α-synuclein as a factor that could modulate disassembly of toxic amyloids by the human disaggregase, a combination of the chaperones Hsc70, DnaJB1 and Apg2. We find that, in contrast to aggregates of the protein lacking the N-terminus, which can be solubilized as efficiently as those of the WT protein, the deletion of the C-terminal domain, either in a recombinant context or as a consequence of calpain treatment, impaired Hsc70-mediated amyloid disassembly. Progressive removal of the negative charges at the C-terminal region induces lateral association of fibrils and type B* oligomers, precluding chaperone action. We propose that truncation-driven aggregate clumping impairs the mechanical action of chaperones, which includes fast protofilament unzipping coupled to depolymerization. Inhibition of the chaperone-mediated clearance of C-truncated species could explain their exacerbated toxicity and higher propensity to deposit found in vivo.

Keywords:  Hsp40; Hsp70; amyloid disassembly; chaperone; human disaggregase; suprafibrillar assemblies; α-synuclein

DOI:  https://doi.org/10.3390/ijms222312983
J Chem Theory Comput. 2021 Dec 09.

Probing Interplays between Human XBP1u Translational Arrest Peptide and 80S Ribosome.

Francesco Di Palma, Sergio Decherchi, Fátima Pardo-Avila, Sauro Succi, Michael Levitt, Gunnar von Heijne, Andrea Cavalli.

The ribosome stalling mechanism is a crucial biological process, yet its atomistic underpinning is still elusive. In this framework, the human XBP1u translational arrest peptide (AP) plays a central role in regulating the unfolded protein response (UPR) in eukaryotic cells. Here, we report multimicrosecond all-atom molecular dynamics simulations designed to probe the interactions between the XBP1u AP and the mammalian ribosome exit tunnel, both for the wild type AP and for four mutant variants of different arrest potencies. Enhanced sampling simulations allow investigating the AP release process of the different variants, shedding light on this complex mechanism. The present outcomes are in qualitative/quantitative agreement with available experimental data. In conclusion, we provide an unprecedented atomistic picture of this biological process and clear-cut insights into the key AP-ribosome interactions.

DOI: https://doi.org/10.1021/acs.jctc.1c00796
PLoS One. 2021 ;16(12): e0260123

Serum supplementation during bovine embryo culture affects their development and proliferation through macroautophagy and endoplasmic reticulum stress regulation.

Edgar Joel Soto-Moreno, Ahmed Balboula, Christine Spinka, Rocío Melissa Rivera.

Serum supplementation during bovine embryo culture has been demonstrated to promote cell proliferation and preimplantation embryo development. However, these desirable outcomes, have been associated with gene expression alterations of pathways involved in macroautophagy, growth, and development at the blastocyst stage, as well as with developmental anomalies such as fetal overgrowth and placental malformations. In order to start dissecting the molecular pathways by which serum supplementation of the culture medium during the preimplantation stage promotes developmental abnormalities, we examined blastocyst morphometry, inner cell mass and trophectoderm cell allocations, macroautophagy, and endoplasmic reticulum stress. On day 5 post-insemination, > 16 cells embryos were selected and cultured in medium containing 10% serum or left as controls. Embryo diameter, inner cell mass and trophectoderm cell number, and macroautophagy were measured on day 8 blastocysts (BL) and expanded blastocysts (XBL). On day 5 and day 8, we assessed transcript level of the ER stress markers HSPA5, ATF4, MTHFD2, and SHMT2 as well as XBP1 splicing (a marker of the unfolded protein response). Serum increased diameter and proliferation of embryos when compared to the no-serum group. In addition, serum increased macroautophagy of BL when compared to controls, while the opposite was true for XBL. None of the genes analyzed was differentially expressed at any stage, except that serum decreased HSPA5 in day 5 > 16 cells stage embryos. XBP1 splicing was decreased in BL when compared to XBL, but only in the serum group. Our data suggest that serum rescues delayed embryos by alleviating endoplasmic reticulum stress and promotes development of advanced embryos by decreasing macroautophagy.

DOI: https://doi.org/10.1371/journal.pone.0260123
J Alzheimers Dis Rep. 2021 ;5(1): 749-760

Neuronal Deposition of Amyloid-β Oligomers and Hyperphosphorylated Tau Is Closely Connected with Cognitive Dysfunction in Aged Dogs.

Umma Habiba, Makiko Ozawa, James K Chambers, Kazuyuki Uchida, Joseph Descallar, Hiroyuki Nakayama, Brian A Summers, John W Morley, Mourad Tayebi.

   Background: Canine cognitive dysfunction (CCD) is a progressive syndrome recognized in mature to aged dogs with a variety of neuropathological changes similar to human Alzheimer's disease (AD), for which it is thought to be a good natural model. However, the presence of hyperphosphorylated tau protein (p-Tau) in dogs with CCD has only been demonstrated infrequently.
Objective: The aim of the present study was to investigate the presence of p-Tau and amyloid-β oligomer (Aβo) in cerebral cortex and hippocampus of dogs with CCD, with focus on an epitope retrieval protocol to unmask p-Tau.
Methods: Immunohistochemical and immunofluorescence analysis of the cortical and hippocampal regions of five CCD-affected and two nondemented aged dogs using 4G8 anti-Aβp, anti-Aβ1 - 42 nanobody (PrioAD13) and AT8 anti-p-Tau (Ser202, Thr205) antibody were used to demonstrate the presence of Aβ plaques (Aβp) and Aβ1 - 42 oligomers and p-Tau deposits, respectively.
Results: The extracellular Aβ senile plaques were of the diffuse type which lack the dense core normally seen in human AD. While p-Tau deposits displayed a widespread pattern and closely resembled the typical human neuropathology, they did not co-localize with the Aβp. Of considerable interest, however, widespread intraneuronal deposition of Aβ1 - 42 oligomers were exhibited in the frontal cortex and hippocampal region that co-localized with p-Tau.
Conclusion: Taken together, these findings reveal further shared neuropathologic features of AD and CCD, supporting the case that aged dogs afflicted with CCD offer a relevant model for investigating human AD.

Keywords:  Alzheimer’s disease; Aβ1 - 42 oligomers; amyloid-β plaques; canine cognitive dysfunction; hyperphosphorylated tau

DOI:  https://doi.org/10.3233/ADR-210035
Neurobiol Aging. 2021 Oct 30. pii: S0197-4580(21)00327-4. [Epub ahead of print]110 73-76

Expression and proteolytic processing of the amyloid precursor protein is unaffected by the expression of the three human apolipoprotein E alleles in the brains of mice.

Mariah J Novy, Samantha F Newbury, Braison Liemisa, Jose Morales-Corraliza, Melissa J Alldred, Stephen D Ginsberg, Paul M Mathews.

  The 3 human apolipoprotein E (APOE) gene alleles modify an individual's risk of developing Alzheimer's disease (AD): compared to the risk-neutral APOE ε3 allele, the ε4 allele (APOE4) is strongly associated with increased AD risk while the ε2 allele is protective. Multiple mechanisms have been shown to link APOE4 expression and AD risk, including the possibility that APOE4 increases the expression of the amyloid precursor protein (APP) (Y-W.A. Huang, B. Zhou, A.M. Nabet, M. Wernig, T.C. Südhof, 2019). In this study, we investigated the impact of APOE genotype on the expression, and proteolytic processing of endogenously expressed APP in the brains of mice humanized for the 3 APOE alleles. In contrast to prior studies using neuronal cultures, we found in the brain that both App gene expression, and the levels of APP holoprotein were not affected by APOE genotype. Additionally, our analysis of APP fragments showed that APOE genotype does not impact APP processing in the brain: the levels of both α- and β-cleaved soluble APP fragments (sAPPs) were similar across genotypes, as were the levels of the membrane-associated α- and β-cleaved C-terminal fragments (CTFs) of APP. Lastly, APOE genotype did not impact the level of soluble amyloid beta (Aβ). These findings argue that the APOE-allele-dependent AD risk is independent of the brain expression and processing of APP.

Keywords:  Alzheimer's disease; Apolipoprotein e; App

DOI:  https://doi.org/10.1016/j.neurobiolaging.2021.10.015
Cureus. 2021 Nov;13(11): e20042

Role of Autophagy in Cardiovascular Disease and Aging.

Christos Koutouroushis, Oiendrila Sarkar.

  Cardiovascular disease is the leading cause of death worldwide and is expected to further increase as people continue to live even longer. Although the life span of the general population is increasing, the con of such a prolonged life span is that aging has certain detrimental effects on the molecular, structural, and functional elements of the cardiovascular system. This review will discuss various molecular pathways linked to longevity, most notably autophagy and its associated mechanisms, and how these pathways can be targeted to promote cardiovascular health through the process of aging. It is to be noted that the process of autophagy decreases with aging; hence, this review concludes that the promotion of autophagy, through implementation of caloric restriction, intermittent fasting, and pharmacologic agents, has proven to be an efficacious means of stimulating cardiovascular health. Therefore, autophagy is an important target for prevention and procrastination of cardiovascular pathologies in the geriatric population.

Keywords:  ampk; autophagy; caloric-restriction; cellular aging; igf-1 signalling; mtor; risk factors of cardiovascular diseases; sirtuins; therapeutic fasting

DOI:  https://doi.org/10.7759/cureus.20042
Nat Cell Biol. 2021 Dec 07.

Reciprocal regulation of chaperone-mediated autophagy and the circadian clock.

Yves R Juste, Susmita Kaushik, Mathieu Bourdenx, Ranee Aflakpui, Sanmay Bandyopadhyay, Fernando Garcia, Antonio Diaz, Kristen Lindenau, Vincent Tu, Gregory J Krause, Maryam Jafari, Rajat Singh, Javier Muñoz, Fernando Macian, Ana Maria Cuervo.

Circadian rhythms align physiological functions with the light-dark cycle through oscillatory changes in the abundance of proteins in the clock transcriptional programme. Timely removal of these proteins by different proteolytic systems is essential to circadian strength and adaptability. Here we show a functional interplay between the circadian clock and chaperone-mediated autophagy (CMA), whereby CMA contributes to the rhythmic removal of clock machinery proteins (selective chronophagy) and to the circadian remodelling of a subset of the cellular proteome. Disruption of this autophagic pathway in vivo leads to temporal shifts and amplitude changes of the clock-dependent transcriptional waves and fragmented circadian patterns, resembling those in sleep disorders and ageing. Conversely, loss of the circadian clock abolishes the rhythmicity of CMA, leading to pronounced changes in the CMA-dependent cellular proteome. Disruption of this circadian clock/CMA axis may be responsible for both pathways malfunctioning in ageing and for the subsequently pronounced proteostasis defect.

DOI: https://doi.org/10.1038/s41556-021-00800-z
IUBMB Life. 2021 Dec 10.

Mitophagy in aging and longevity.

Jing Guo, Wei-Chung Chiang.

  The clearance of damaged or unwanted mitochondria by autophagy (also known as mitophagy) is a mitochondrial quality control mechanism postulated to play an essential role in cellular homeostasis, metabolism, and development and confers protection against a wide range of diseases. Proper removal of damaged or unwanted mitochondria is essential for organismal health. Defects in mitophagy are associated with Parkinson's, Alzheimer's disease, cancer, and other degenerative disorders. Mitochondria regulate organismal fitness and longevity via multiple pathways, including cellular senescence, stem cell function, inflammation, mitochondrial unfolded protein response (mtUPR), and bioenergetics. Thus, mitophagy is postulated to be pivotal for maintaining organismal healthspan and lifespan and the protection against aged-related degeneration. In this review, we will summarize recent understanding of the mechanism of mitophagy and aspects of mitochondrial functions. We will focus on mitochondria-related cellular processes that are linked to aging and examine current genetic evidence that supports the hypothesis that mitophagy is a pro-longevity mechanism.

Keywords:  aging; longevity; mitophagy

DOI:  https://doi.org/10.1002/iub.2585
Nature. 2021 Dec 08.

Aggregates of TDP-43 protein spiral into view.

Hana M Odeh, James Shorter.



Keywords:  Neurodegeneration; Structural biology

DOI:  https://doi.org/10.1038/d41586-021-03605-0
J Alzheimers Dis. 2021 Nov 30.

Sex Differences in Behavior and Molecular Pathology in the 5XFAD Model.

Annesha Sil, Arina Erfani, Nicola Lamb, Rachel Copland, Gernot Riedel, Bettina Platt.

   BACKGROUND: The prevalence of Alzheimer's disease (AD) is greater in women compared to men, but the reasons for this remain unknown. This sex difference has been widely neglected in experimental studies using transgenic mouse models of AD.
OBJECTIVE: Here, we studied behavior and molecular pathology of 5-month-old 5XFAD mice, which express mutated human amyloid precursor protein and presenilin-1 on a C57BL/6J background, versus their wild-type littermate controls, to compared both sex- and genotype-dependent differences.
METHODS: A novel behavioral paradigm was utilized (OF-NO-SI), comprising activity measures (Open Field, OF) arena, followed by Novel Object exploration (NO) and Social Interaction (SI) of a sex-matched conspecific. Each segment consisted of two repeated trials to assess between-trial habituation. Subsequently, brain pathology (amyloid load, stress response and inflammation markers, synaptic integrity, trophic support) was assessed using qPCR and western blotting.
RESULTS: Female 5XFAD mice had higher levels of human APP and amyloid-β and heightened inflammation versus males. These markers correlated with hyperactivity observed in both sexes, yet only female 5XFAD mice presented with deficits in object and social exploration. Male animals had higher expression of stress markers and neurotrophic factors irrespective of genotype, this correlated with cognitive performance.
CONCLUSION: The impact of sex on AD-relevant phenotypes is in line with human data and emphasizes the necessity of appropriate study design and reporting. Differential molecular profiles observed in male versus female mice offer insights into possible protective mechanisms, and hence treatment strategies.

Keywords:  Activity; ER stress; amyloid-β; cognition; female; inflammation; male; social; trophic factors

DOI:  https://doi.org/10.3233/JAD-210523
Proc Natl Acad Sci U S A. 2021 Dec 07. pii: e2108163118. [Epub ahead of print]118(49):

Class-specific interactions between Sis1 J-domain protein and Hsp70 chaperone potentiate disaggregation of misfolded proteins.

Hubert Wyszkowski, Anna Janta, Wiktoria Sztangierska, Igor Obuchowski, Tomasz Chamera, Agnieszka Kłosowska, Krzysztof Liberek.

  Protein homeostasis is constantly being challenged with protein misfolding that leads to aggregation. Hsp70 is one of the versatile chaperones that interact with misfolded proteins and actively support their folding. Multifunctional Hsp70s are harnessed to specific roles by J-domain proteins (JDPs, also known as Hsp40s). Interaction with the J-domain of these cochaperones stimulates ATP hydrolysis in Hsp70, which stabilizes substrate binding. In eukaryotes, two classes of JDPs, Class A and Class B, engage Hsp70 in the reactivation of aggregated proteins. In most species, excluding metazoans, protein recovery also relies on an Hsp100 disaggregase. Although intensely studied, many mechanistic details of how the two JDP classes regulate protein disaggregation are still unknown. Here, we explore functional differences between the yeast Class A (Ydj1) and Class B (Sis1) JDPs at the individual stages of protein disaggregation. With real-time biochemical tools, we show that Ydj1 alone is superior to Sis1 in aggregate binding, yet it is Sis1 that recruits more Ssa1 molecules to the substrate. This advantage of Sis1 depends on its ability to bind to the EEVD motif of Hsp70, a quality specific to most of Class B JDPs. This second interaction also conditions the Hsp70-induced aggregate modification that boosts its subsequent dissolution by the Hsp104 disaggregase. Our results suggest that the Sis1-mediated chaperone assembly at the aggregate surface potentiates the entropic pulling, driven polypeptide disentanglement, while Ydj1 binding favors the refolding of the solubilized proteins. Such subspecialization of the JDPs across protein reactivation improves the robustness and efficiency of the disaggregation machinery.

Keywords:  Hsp40; chaperones; protein aggregation

DOI:  https://doi.org/10.1073/pnas.2108163118
J Alzheimers Dis. 2021 Dec 01.

High Fat Diet Mediates Amyloid-β Cleaving Enzyme 1 Phosphorylation and SUMOylation, Enhancing Cognitive Impairment in APP/PS1 Mice.

Jian Bao, Zheng Liang, Xiaokang Gong, Jing Yu, Yifan Xiao, Wei Liu, Xiaochuan Wang, Jian-Zhi Wang, Xiji Shu.

   BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia in older adults and extracellular accumulation of amyloid-β (Aβ) is one of the two characterized pathologies of AD. Obesity is significantly associated with AD developing factors. Several studies have reported that high fat diet (HFD) influenced Aβ accumulation and cognitive performance during AD pathology. However, the underlying neurobiological mechanisms have not yet been elucidated.
OBJECTIVE: The objective of this study was to explore the underlying neurobiological mechanisms of HFD influenced Aβ accumulation and cognitive performance during AD pathology.
METHODS: 2.5-month-old male APP/PS1 mice were randomly separated into two groups: 1) the normal diet (ND) group, fed a standard diet (10 kcal%fat); and 2) the HFD group, fed a high fat diet (40 kcal%fat, D12492; Research Diets). After 4 months of HFD or ND feeding, mice in the two groups were subjected for further ethological, morphological, and biochemical analyses.
RESULTS: A long-term HFD diet significantly increased perirenal fat and impaired dendritic integrity and aggravated neurodegeneration, and augmented learning and memory deficits in APP/PS1 mice. Furthermore, the HFD increased beta amyloid cleaving enzyme 1 (BACE1) dephosphorylation and SUMOylation, resulting in enhanced enzyme activity and stability, which exacerbated the deposition of amyloid plaques.
CONCLUSION: Our study demonstrates that long-term HFD consumption aggravates amyloid-β accumulation and cognitive impairments, and that modifiable lifestyle factors, such as obesity, can induce BACE1 post-modifications which may contribute to AD pathogenesis.

Keywords:  Alzheimer’s disease; BACE1; SUMOylation; high fat; phosphorylation

DOI:  https://doi.org/10.3233/JAD-215299
Neurobiol Aging. 2021 Nov 11. pii: S0197-4580(21)00331-6. [Epub ahead of print]110 77-87

Comparing anti-aging hallmark activities of Metformin and Nano-PSO in a mouse model of genetic Creutzfeldt-Jakob Disease.

Orli Binyamin, Kati Frid, Guy Keller, Ann Saada, Ruth Gabizon.

  Advanced age is the main risk factor for the manifestation of late onset neurodegenerative diseases. Metformin, an anti-diabetic drug, was shown to extend longevity, and to ameliorate the activity of recognized aging hallmarks. Here, we compared the clinical, pathologic and biochemical effects of Metformin to those of Nano-PSO (Granagard), a brain targeted anti-oxidant shown by us to delay disease advance in transgenic mice mimicking for genetic Creutzfeldt Jacob disease (CJD) linked to the E200KPrP mutation. We demonstrate that both Metformin and Nano-PSO reduced aging hallmarks activities such as activated AMPK, the main energy sensor of cells as well as Nrf2 and COX IV1, regulators of oxidation, and mitochondrial activity. Both compounds reduced inflammation and increased stem cells production, however did not decrease PrP accumulation. As opposed to Nano-PSO, Metformin neither delayed clinical disease advance in these mice nor reduced the accumulation of sulfated glycosaminoglycans, a pathologic feature of prion disease. We conclude that elevation of anti-aging markers may not be sufficient to delay the fatal advance of genetic CJD.

Keywords:  AMPK; Aging; Genetic CJD; Granagard; Metformin; Nano-PSO; Neurodegeneration; Prion

DOI:  https://doi.org/10.1016/j.neurobiolaging.2021.11.001