bims-proarb 2022-05-01 papers

bims-proarb

Biomed News

on Proteostasis in aging and regenerative biology

Issue of 2022–05–01
fiveteen papers selected by
Rich Giadone, Harvard University

Emerging roles of endoplasmic reticulum proteostasis in brain development.
Reducing ER stress with chaperone therapy reverses sleep fragmentation and cognitive decline in aged mice.
Pharmacological activation of ATF6 remodels the proteostasis network to rescue pathogenic GABAA receptors.
Comparative study of protein aggregation propensity and mutation tolerance between naked mole-rat and mouse.
The dynamic effect of genetic variation on the in vivo ER stress transcriptional response in different tissues.
Control of human protein-degradation machinery revealed.
The PERKs of mitochondria protection during stress: insights for PERK modulation in neurodegenerative and metabolic diseases.
Small Heat Shock Proteins in Retinal Diseases.
APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer's disease with Lewy body pathology.
Transcriptional lockdown during acute proteotoxic stress.
Chloroplast protein import machinery and quality control.
Cellular Reprogramming and Its Potential Application in Alzheimer's Disease.
The endoplasmic reticulum adopts two distinct tubule forms.
Prediction of disordered regions in proteins with recurrent Neural Networks and protein dynamics.
Dynamics of ubiquitination in differentiation and dedifferentiation of pancreatic β-cells: Putative Target for Diabetes.

Cells Dev. 2022 Apr 25. pii: S2667-2901(22)00017-1. [Epub ahead of print] 203781

Emerging roles of endoplasmic reticulum proteostasis in brain development.

Giselle Espinosa Vásquez, Danilo B Medinas, Hery Urra, Claudio Hetz.

  The development of the central nervous system requires a series of morphogenetic events that shape brain and spinal cord structures. Several brain regions and neural circuits are formed by differential gene expression patterns and cell migration events involving neurons. During neurogenesis and neuritogenesis, increased demand for protein synthesis occurs to express key neuronal proteins to generate axons, dendrites, and active synapsis. The endoplasmic reticulum (ER) is a central hub controlling protein homeostasis (proteostasis), impacting a wide range of cellular processes required for brain function. Although most of the field has focused on ER stress in neurodegenerative diseases marked by abnormal protein aggregation, accumulating evidence indicates that ER proteostasis contributes to brain development impacting processes such as neuronal migration, differentiation, and function. Here, we review emerging evidence linking neurodevelopment with ER proteostasis and its relevance to human disorders.

Keywords:  Brain development; Chaperones; Endoplasmic reticulum; Neurodevelopmental disorders; Proteostasis; Unfolded protein response

DOI:  https://doi.org/10.1016/j.cdev.2022.203781
Aging Cell. 2022 Apr 30. e13598

Reducing ER stress with chaperone therapy reverses sleep fragmentation and cognitive decline in aged mice.

Jennifer M Hafycz, Ewa Strus, Nirinjini Naidoo.

  As the aging population grows, the need to understand age-related changes in health is vital. Two prominent behavioral changes that occur with age are disrupted sleep and impaired cognition. Sleep disruptions lead to perturbations in proteostasis and endoplasmic reticulum (ER) stress in mice. Further, consolidated sleep and protein synthesis are necessary for memory formation. With age, the molecular mechanisms that relieve cellular stress and ensure proper protein folding become less efficient. It is unclear if a causal relationship links proteostasis, sleep quality, and cognition in aging. Here, we used a mouse model of aging to determine if supplementing chaperone levels reduces ER stress and improves sleep quality and memory. We administered the chemical chaperone 4-phenyl butyrate (PBA) to aged and young mice, and monitored sleep and cognitive behavior. We found that chaperone treatment consolidates sleep and wake, and improves learning in aged mice. These data correlate with reduced ER stress in the cortex and hippocampus of aged mice. Chaperone treatment increased p-CREB, which is involved in memory formation and synaptic plasticity, in hippocampi of chaperone-treated aged mice. Hippocampal overexpression of the endogenous chaperone, binding immunoglobulin protein (BiP), improved cognition, reduced ER stress, and increased p-CREB in aged mice, suggesting that supplementing BiP levels are sufficient to restore some cognitive function. Together, these results indicate that restoring proteostasis improves sleep and cognition in a wild-type mouse model of aging. The implications of these results could have an impact on the development of therapies to improve health span across the aging population.

Keywords:  aging; anti-aging; behavior; molecular biology of aging; mouse models; neuroscience

DOI:  https://doi.org/10.1111/acel.13598
Cell Biosci. 2022 Apr 27. 12(1): 48

Pharmacological activation of ATF6 remodels the proteostasis network to rescue pathogenic GABAA receptors.

Meng Wang, Edmund Cotter, Ya-Juan Wang, Xu Fu, Angela L Whittsette, Joseph W Lynch, R Luke Wiseman, Jeffery W Kelly, Angelo Keramidas, Ting-Wei Mu.

BACKGROUND: Genetic variants in the subunits of the gamma-aminobutyric acid type A (GABAA) receptors are implicated in the onset of multiple pathologic conditions including genetic epilepsy. Previous work showed that pathogenic GABAA subunits promote misfolding and inefficient assembly of the GABAA receptors, limiting receptor expression and activity at the plasma membrane. However, GABAA receptors containing variant subunits can retain activity, indicating that enhancing the folding, assembly, and trafficking of these variant receptors offers a potential opportunity to mitigate pathology associated with genetic epilepsy.
RESULTS: Here, we demonstrate that pharmacologically enhancing endoplasmic reticulum (ER) proteostasis using small molecule activators of the ATF6 (Activating Transcription Factor 6) signaling arm of the unfolded protein response (UPR) increases the assembly, trafficking, and surface expression of variant GABAA receptors. These improvements are attributed to ATF6-dependent remodeling of the ER proteostasis environment, which increases protein levels of pro-folding ER proteostasis factors including the ER chaperone BiP (Immunoglobulin Binding Protein) and trafficking receptors, such as LMAN1 (Lectin Mannose-Binding 1) and enhances their interactions with GABAA receptors. Importantly, we further show that pharmacologic ATF6 activators increase the activity of GABAA receptors at the cell surface, revealing the potential for this strategy to restore receptor activity to levels that could mitigate disease pathogenesis.
CONCLUSIONS: These results indicate that pharmacologic ATF6 activators offer an opportunity to restore GABAA receptor activity in diseases including genetic epilepsy and point to the potential for similar pharmacologic enhancement of ER proteostasis to improve trafficking of other disease-associated variant ion channels implicated in etiologically-diverse diseases.

DOI: https://doi.org/10.1186/s13578-022-00783-w
Genome Biol Evol. 2022 Apr 28. pii: evac057. [Epub ahead of print]

Comparative study of protein aggregation propensity and mutation tolerance between naked mole-rat and mouse.

Savandara Besse, Raphaël Poujol, Julie G Hussin.

  The molecular mechanisms of aging and life expectancy have been studied in model organisms with short lifespans. However, long-lived species may provide insights into successful strategies for healthy aging, potentially opening the door for novel therapeutic interventions in age-related diseases. Notably, naked mole-rats, the longest-lived rodent, present attenuated aging phenotypes compared to mice. Their resistance toward oxidative stress has been proposed as one hallmark of their healthy aging, suggesting their ability to maintain cell homeostasis, specifically their protein homeostasis. To identify the general principles behind their protein homeostasis robustness, we compared the aggregation propensity and mutation tolerance of naked mole-rat and mouse orthologous proteins. Our analysis showed no proteome-wide differential effects in aggregation propensity and mutation tolerance between these species, but several subsets of proteins with a significant difference in aggregation propensity. We found an enrichment of proteins with higher aggregation propensity in naked mole-rat, and these are functionally involved in the inflammasome complex and nucleic acid binding. On the other hand, proteins with lower aggregation propensity in naked mole-rat have a significantly higher mutation tolerance compared to the rest of the proteins. Among them, we identified proteins known to be associated with neurodegenerative and age-related diseases. These findings highlight the intriguing hypothesis about the capacity of the naked mole-rat proteome to delay aging through its proteomic intrinsic architecture.

Keywords:  aging; longevity; mutation tolerance; naked mole-rat; protein aggregation propensity; protein homeostasis

DOI:  https://doi.org/10.1093/gbe/evac057
G3 (Bethesda). 2022 Apr 29. pii: jkac104. [Epub ahead of print]

The dynamic effect of genetic variation on the in vivo ER stress transcriptional response in different tissues.

Nikki D Russell, Clement Y Chow.

  The genetic regulation of gene expression varies greatly across tissue-type and individuals and can be strongly influenced by the environment. Many variants, under healthy control conditions, may be silent or even have the opposite effect under diseased stress conditions. This study uses an in vivo mouse model to investigate how the effect of genetic variation changes with cellular stress across different tissues. Endoplasmic reticulum (ER) stress occurs when misfolded proteins accumulate in the ER. This triggers the unfolded protein response (UPR), a large transcriptional response which attempts to restore homeostasis. This transcriptional response, despite being a conserved, basic cellular process, is highly variable across different genetic backgrounds, making it an ideal system to study the dynamic effects of genetic variation. In this study, we sought to better understand how genetic variation alters expression across tissues, in the presence and absence of ER stress. The use of different mouse strains and their F1s allow us to also identify context specific cis- and trans- regulatory variation underlying variable transcriptional responses. We found hundreds of genes that respond to ER stress in a tissue- and/or genotype-dependent manner. The majority of the regulatory effects we identified were acting in cis-, which in turn, contribute to the variable ER stress- and tissue-specific transcriptional response. This study demonstrates the need for incorporating environmental stressors across multiple different tissues in future studies to better elucidate the effect of any particular genetic factor in basic biological pathways, like the ER stress response.

Keywords:   in vivo mouse; ER stress; GxE; genetic variation; regulatory variation; tissue effects

DOI:  https://doi.org/10.1093/g3journal/jkac104
Nature. 2022 Apr 27.

Control of human protein-degradation machinery revealed.



Keywords:  Molecular biology; Structural biology

DOI:  https://doi.org/10.1038/d41586-022-01144-w
Biol Rev Camb Philos Soc. 2022 Apr 26.

The PERKs of mitochondria protection during stress: insights for PERK modulation in neurodegenerative and metabolic diseases.

Liliana M Almeida, Brígida R Pinho, Michael R Duchen, Jorge M A Oliveira.

  Protein kinase RNA-like ER kinase (PERK) is an endoplasmic reticulum (ER) stress sensor that responds to the accumulation of misfolded proteins. Once activated, PERK initiates signalling pathways that halt general protein production, increase the efficiency of ER quality control, and maintain redox homeostasis. PERK activation also protects mitochondrial homeostasis during stress. The location of PERK at the contact sites between the ER and the mitochondria creates a PERK-mitochondria axis that allows PERK to detect stress in both organelles, adapt their functions and prevent apoptosis. During ER stress, PERK activation triggers mitochondrial hyperfusion, preventing premature apoptotic fragmentation of the mitochondria. PERK activation also increases the formation of mitochondrial cristae and the assembly of respiratory supercomplexes, enhancing cellular ATP-generating capacity. PERK strengthens mitochondrial quality control during stress by promoting the expression of mitochondrial chaperones and proteases and by increasing mitochondrial biogenesis and mitophagy, resulting in renewal of the mitochondrial network. But how does PERK mediate all these changes in mitochondrial homeostasis? In addition to the classic PERK-eukaryotic translation initiation factor 2α (eIF2α)-activating transcription factor 4 (ATF4) pathway, PERK can activate other protective pathways - PERK-O-linked N-acetyl-glucosamine transferase (OGT), PERK-transcription factor EB (TFEB), and PERK-nuclear factor erythroid 2-related factor 2 (NRF2) - contributing to broader regulation of mitochondrial dynamics, metabolism, and quality control. The pharmacological activation of PERK is protective in models of neurodegenerative and metabolic diseases, such as Huntington's disease, progressive supranuclear palsy and obesity, while the inhibition of PERK was protective in models of Parkinson's and prion diseases and diabetes. In this review, we address the molecular mechanisms by which PERK regulates mitochondrial dynamics, metabolism and quality control, and discuss the therapeutic potential of targeting PERK in neurodegenerative and metabolic diseases.

Keywords:  PERK; dynamics; endoplasmic reticulum; metabolic diseases; metabolism; mitochondria; neurodegeneration; stress; unfolded protein response

DOI:  https://doi.org/10.1111/brv.12860
Front Mol Biosci. 2022 ;9 860375

Small Heat Shock Proteins in Retinal Diseases.

Vivian Rajeswaren, Jeffrey O Wong, Dana Yabroudi, Rooban B Nahomi, Johanna Rankenberg, Mi-Hyun Nam, Ram H Nagaraj.

  This review summarizes the latest findings on small heat shock proteins (sHsps) in three major retinal diseases: glaucoma, diabetic retinopathy, and age-related macular degeneration. A general description of the structure and major cellular functions of sHsps is provided in the introductory remarks. Their role in specific retinal diseases, highlighting their regulation, role in pathogenesis, and possible use as therapeutics, is discussed.

Keywords:  age-related macular degeneration; diabetic retinopathy; glaucoma; retina; small heat shock proteins

DOI:  https://doi.org/10.3389/fmolb.2022.860375
Acta Neuropathol. 2022 Apr 26.

APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer's disease with Lewy body pathology.

Yunjung Jin, Fuyao Li, Berkiye Sonoustoun, Naveen Chandra Kondru, Yuka A Martens, Wenhui Qiao, Michael G Heckman, Tadafumi C Ikezu, Zonghua Li, Jeremy D Burgess, Danilyn Amerna, Justin O'Leary, Michael A DeTure, Jing Zhao, Pamela J McLean, Dennis W Dickson, Owen A Ross, Guojun Bu, Na Zhao.

  Approximately half of Alzheimer's disease (AD) brains have concomitant Lewy pathology at autopsy, suggesting that α-synuclein (α-SYN) aggregation is a regulated event in the pathogenesis of AD. Genome-wide association studies revealed that the ε4 allele of the apolipoprotein E (APOE4) gene, the strongest genetic risk factor for AD, is also the most replicated genetic risk factor for Lewy body dementia (LBD), signifying an important role of APOE4 in both amyloid-β (Aβ) and α-SYN pathogenesis. How APOE4 modulates α-SYN aggregation in AD is unclear. In this study, we aimed to determine how α-SYN is associated with AD-related pathology and how APOE4 impacts α-SYN seeding and toxicity. We measured α-SYN levels and their association with other established AD-related markers in brain samples from autopsy-confirmed AD patients (N = 469), where 54% had concomitant LB pathology (AD + LB). We found significant correlations between the levels of α-SYN and those of Aβ40, Aβ42, tau and APOE, particularly in insoluble fractions of AD + LB. Using a real-time quaking-induced conversion (RT-QuIC) assay, we measured the seeding activity of soluble α-SYN and found that α-SYN seeding was exacerbated by APOE4 in the AD cohort, as well as a small cohort of autopsy-confirmed LBD brains with minimal Alzheimer type pathology. We further fractionated the soluble AD brain lysates by size exclusion chromatography (SEC) ran on fast protein liquid chromatography (FPLC) and identified the α-SYN species (~ 96 kDa) that showed the strongest seeding activity. Finally, using human induced pluripotent stem cell (iPSC)-derived neurons, we showed that amplified α-SYN aggregates from AD + LB brain of patients with APOE4 were highly toxic to neurons, whereas the same amount of α-SYN monomer was not toxic. Our findings suggest that the presence of LB pathology correlates with AD-related pathologies and that APOE4 exacerbates α-SYN seeding activity and neurotoxicity, providing mechanistic insight into how APOE4 affects α-SYN pathogenesis in AD.

Keywords:  Alzheimer’s disease; Apolipoprotein E; Lewy body dementia; RT-QuIC; Seeding; α-synuclein

DOI:  https://doi.org/10.1007/s00401-022-02421-8
Trends Biochem Sci. 2022 Apr 26. pii: S0968-0004(22)00083-4. [Epub ahead of print]

Transcriptional lockdown during acute proteotoxic stress.

Ritwick Sawarkar.

  Cells experiencing proteotoxic stress downregulate the expression of thousands of active genes and upregulate a few stress-response genes. The strategy of downregulating gene expression has conceptual parallels with general lockdown in the global response to the coronavirus disease 2019 (COVID-19) pandemic. The mechanistic details of global transcriptional downregulation of genes, termed stress-induced transcriptional attenuation (SITA), are only beginning to emerge. The reduction in RNA and protein production during stress may spare proteostasis capacity, allowing cells to divert resources to control stress-induced damage. Given the relevance of translational downregulation in a broad variety of diseases, the role of SITA in diseases caused by proteotoxicity should be investigated in future, paving the way for potential novel therapeutics.

Keywords:  NELF; RNA polymerase II; heat shock; proteostasis; transcription

DOI:  https://doi.org/10.1016/j.tibs.2022.03.020
FEBS J. 2022 Apr 26.

Chloroplast protein import machinery and quality control.

Jean-David Rochaix.

  Most chloroplast proteins are nucleus-encoded, translated on cytoplasmic ribosomes as precursor proteins and imported into chloroplasts through TOC and TIC, the translocons of the outer and inner chloroplast envelope membranes. While the composition of the TOC complex is well established, there is still some controversy about the importance of a recently identified TIC complex consisting of Tic20, Tic214, Tic100 and Tic56. TOC and TIC form a supercomplex with a protein channel at the junction of the outer and inner envelope membranes through which preproteins are pulled into the stroma by the ATP-powered Ycf2 complex consisting of several FtsH-like ATPases and/or by chloroplast Hsp proteins. Several components of the TOC/TIC system are moonlighting proteins with additional roles in chloroplast gene expression and metabolism. Chaperones and co-chaperones, associated with TOC and TIC on the cytoplasmic and stromal side of the chloroplast envelope, participate in the unfolding and folding of the precursor proteins and act together with the ubiquitin proteasome system in protein quality control. Chloroplast protein import is also intimately linked with retrograde signaling, revealing altogether an unsuspected complexity in the regulation of this process.

Keywords:  autophagy; chloroplast; protein aggregation; protein import; retrograde signaling; translocon; ubiquitin proteasome system; unfolded protein response

DOI:  https://doi.org/10.1111/febs.16464
Front Neurosci. 2022 ;16 884667

Cellular Reprogramming and Its Potential Application in Alzheimer's Disease.

Chao Zhou, Wanyan Ni, Taiyang Zhu, Shuyu Dong, Ping Sun, Fang Hua.

  Alzheimer's disease (AD) has become the most common age-related dementia in the world and is currently incurable. Although many efforts have been made, the underlying mechanisms of AD remain unclear. Extracellular amyloid-beta deposition, intracellular tau hyperphosphorylation, neuronal death, glial cell activation, white matter damage, blood-brain barrier disruption, and other mechanisms all take part in this complicated disease, making it difficult to find an effective therapy. In the study of therapeutic methods, how to restore functional neurons and integrate myelin becomes the main point. In recent years, with the improvement and maturity of induced pluripotent stem cell technology and direct cell reprogramming technology, it has become possible to induce non-neuronal cells, such as fibroblasts or glial cells, directly into neuronal cells in vitro and in vivo. Remarkably, the induced neurons are functional and capable of entering the local neural net. These encouraging results provide a potential new approach for AD therapy. In this review, we summarized the characteristics of AD, the reprogramming technique, and the current research on the application of cellular reprogramming in AD. The existing problems regarding cellular reprogramming and its therapeutic potential for AD were also reviewed.

Keywords:  Alzheimer’s disease; cellular reprogramming; iPSCs; neurological function; neuroregeneration

DOI:  https://doi.org/10.3389/fnins.2022.884667
Proc Natl Acad Sci U S A. 2022 May 03. 119(18): e2117559119

The endoplasmic reticulum adopts two distinct tubule forms.

Bowen Wang, Zhiheng Zhao, Michael Xiong, Rui Yan, Ke Xu.

  SignificanceThe endoplasmic reticulum (ER) is one of the most structurally visible and functionally important organelles in the cell. Utilizing superresolution microscopy, we here unveil that in the mammalian cell, the peripheral ER adopts two distinct, well-defined tubule forms of contrasting structures, molecular signatures, and functions, with one of the two curiously being ribbon-like, ultranarrow sheets of fixed widths. With fast multicolor microscopy, we further show how the two tubule forms dynamically interconvert while differentially accommodating proteins in the living cell.

Keywords:  ER tubules; ER-shaping proteins; endoplasmic reticulum; organelle morphology; superresolution microscopy

DOI:  https://doi.org/10.1073/pnas.2117559119
J Mol Biol. 2022 Apr 22. pii: S0022-2836(22)00159-0. [Epub ahead of print] 167579

Prediction of disordered regions in proteins with recurrent Neural Networks and protein dynamics.

Gabriele Orlando, Daniele Raimondi, Francesco Codice, Francesco Tabaro, Wim Vranken.

  The role of intrinsically disordered protein regions (IDRs) in cellular processes has become increas- ingly evident over the last years. These IDRs continue to challenge structural biology experiments be- cause they lack a well-defined conformation, and bioinformatics approaches that accurately delineate dis- ordered protein regions remain essential for their identification and further investigation. Typically, these predictors use the protein amino acid sequence, without taking into account likely sequence-dependent emergent properties, such as protein backbone dynamics. Here we present DisoMine, a method that predicts protein 'long disorder' with recurrent neural net- works from simple predictions of protein dynamics, secondary structure and early folding. The tool is fast and requires only a single sequence, making it applicable for large-scale screening, including poorly studied and orphan proteins. DisoMine is a top performer in its category and compares well to disorder prediction approaches using evolutionary information. DisoMine is freely available through an interactive webserver at https://bio2byte.be/disomine/.

Keywords:  intrinsically disordered proteins; machine learning; neural networks; protein backbone dynamics; protein disorder prediction

DOI:  https://doi.org/10.1016/j.jmb.2022.167579
Curr Protein Pept Sci. 2022 Apr 22.

Dynamics of ubiquitination in differentiation and dedifferentiation of pancreatic β-cells: Putative Target for Diabetes.

Meenal Francis, Smitha Bhaskar, Sreya Vishnuvajhala, Jyothi Prasanna, Anujith Kumar.

  Impairment in the function of insulin-producing pancreatic β-cells is a hallmark of both type 1 and 2 diabetes (T1D/T2D). Despite nearly a century of efforts to combat acute diabetes burden, there is yet no precise treatment regimen existing. Enhancing the endogenous β-cells either by protecting them from apoptosis or dedifferentiation is a classic alternative approach to retain the β-cell pool. Recent reports have acknowledged the protein homeostasis mediated by the ubiquitin-proteasome system as one of the essential components in maintaining the β-cell pool. Degradation of the targeted substrate by the proteasome is majorly regulated by the ubiquitination status of the targeted protein dictated by E3 ligases and deubiquitinase enzymes. Imbalance in the function of these enzymes results in the malfunction of β-cells and in turn, hyperglycemia. Ubiquitination involves the covalent attachment of one or more ubiquitin moieties to the target protein by E3 ubiquitin ligases and deubiquitinases (DUBs) are the enzymes which antagonize the action of E3 ligases. Having knowledge about different E3 ligases and deubiquitinases in the process of differentiation and dedifferentiation of β-cells, probably paves the way for designing novel modulators that enhance either the differentiation or abate the dedifferentiation process. In this review, we will discuss the importance of the balanced ubiquitination process, an understanding of which would facilitate the restraining of β-cells from exhaustion.

Keywords:  Diabetes; Intracellular protein degradation; Proteasome; dedifferentiation; differentiation; pancreas

DOI:  https://doi.org/10.2174/1389203723666220422092023