bims-proarb 2021-09-05 papers

bims-proarb

Biomed News

on Proteostasis in aging and regenerative biology

Issue of 2021‒09‒05
twenty-four papers selected by
Rich Giadone
Harvard University

The role of endoplasmic reticulum stress in astrocytes.
Insulin/IGF-1 signaling and heat stress differentially regulate HSF1 activities in germline development.
Neuronal regulated ire-1-dependent mRNA decay controls germline differentiation in Caenorhabditis elegans.
Tau Abnormalities and Autophagic Defects in Neurodegenerative Disorders; A Feed-forward Cycle.
Acute heat stress alters the expression of genes and proteins associated with the unfolded protein response pathway in the liver of broilers.
Interplay between mammalian heat shock factors 1 and 2 in physiology and pathology.
Protein disulphide isomerase (PDI) is protective against amyotrophic lateral sclerosis (ALS)-related mutant Fused in Sarcoma (FUS) in in vitro models.
The mitochondrial permeability transition pore activates the mitochondrial unfolded protein response and promotes aging.
Neuromyelitis optica (NMO)-IgG-driven organelle reorganization in human iPSC-derived astrocytes.
Autophagy in major human diseases.
Improved modeling of human AD with an automated culturing platform for iPSC neurons, astrocytes and microglia.
Endoplasmic reticulum tubules limit the size of misfolded protein condensates.
Extracellular protein components of amyloid plaques and their roles in Alzheimer's disease pathology.
Functional characterization of T2D-associated SNP effects on baseline and ER stress-responsive β cell transcriptional activation.
Mitochondrial links between brain aging and Alzheimer's disease.
Long-term depression links amyloid-β to the pathological hyperphosphorylation of tau.
Patient-specific iPSCs carrying an SFTPC mutation reveal the intrinsic alveolar epithelial dysfunction at the inception of interstitial lung disease.
A Comprehensive Insight into the Mechanisms of Dopamine in Disrupting Aβ Protofibrils and Inhibiting Aβ Aggregation.
A (dis)integrated stress response: Genetic diseases of eIF2α regulators.
A mass spectrometric approach to study the interaction of amyloid β peptides with human α-2-macroglobulin.
Decreased autophagy impairs osteogenic differentiation of adipose-derived stem cells via Notch signaling in diabetic osteoporosis mice.
Einstein-Nathan Shock Center: translating the hallmarks of aging to extend human health span.
Involvement of autophagy in diosgenin‑induced megakaryocyte differentiation in human erythroleukemia cells.
Protein degradation profile reveals dynamic nature of 20S proteasome small molecule stimulation.

Glia. 2021 Aug 31.

The role of endoplasmic reticulum stress in astrocytes.

Savannah G Sims, Rylee N Cisney, Marissa M Lipscomb, Gordon P Meares.

  Astrocytes are glial cells that support neurological function in the central nervous system (CNS), in part, by providing structural support for neuronal synapses and blood vessels, participating in electrical and chemical transmission, and providing trophic support via soluble factors. Dysregulation of astrocyte function contributes to neurological decline in CNS diseases. Neurological diseases are highly heterogeneous but share common features of cellular stress including the accumulation of misfolded proteins. Endoplasmic reticulum (ER) stress has been reported in nearly all neurological and neurodegenerative diseases. ER stress occurs when there is an accumulation of misfolded proteins in the ER lumen and the protein folding demand of the ER is overwhelmed. ER stress initiates the unfolded protein response (UPR) to restore homeostasis by abating protein translation and, if the cell is irreparably damaged, initiating apoptosis. Although protein aggregation and misfolding in neurological disease has been well described, cell-specific contributions of ER stress and the UPR in physiological and disease states are poorly understood. Recent work has revealed a role for active UPR signaling that may drive astrocytes toward a maladaptive phenotype in various model systems. In response to ER stress, astrocytes produce inflammatory mediators, have reduced trophic support, and can transmit ER stress to other cells. This review will discuss the current known contributions and consequences of activated UPR signaling in astrocytes.

Keywords:  astrocytes; cell signaling; endoplasmic reticulum; glia; protein folding; translation

DOI:  https://doi.org/10.1002/glia.24082
Cell Rep. 2021 Aug 31. pii: S2211-1247(21)01061-5. [Epub ahead of print]36(9): 109623

Insulin/IGF-1 signaling and heat stress differentially regulate HSF1 activities in germline development.

Stacey L Edwards, Purevsuren Erdenebat, Allison C Morphis, Lalit Kumar, Lai Wang, Tomasz Chamera, Constantin Georgescu, Jonathan D Wren, Jian Li.

  Germline development is sensitive to nutrient availability and environmental perturbation. Heat shock transcription factor 1 (HSF1), a key transcription factor driving the cellular heat shock response (HSR), is also involved in gametogenesis. The precise function of HSF1 (HSF-1 in C. elegans) and its regulation in germline development are poorly understood. Using the auxin-inducible degron system in C. elegans, we uncovered a role of HSF-1 in progenitor cell proliferation and early meiosis and identified a compact but important transcriptional program of HSF-1 in germline development. Interestingly, heat stress only induces the canonical HSR in a subset of germ cells but impairs HSF-1 binding at its developmental targets. Conversely, insulin/insulin growth factor 1 (IGF-1) signaling dictates the requirement for HSF-1 in germline development and functions through repressing FOXO/DAF-16 in the soma to activate HSF-1 in germ cells. We propose that this non-cell-autonomous mechanism couples nutrient-sensing insulin/IGF-1 signaling to HSF-1 activation to support homeostasis in rapid germline growth.

Keywords:  HSF1; germline development; heat shock response; insulin/IGF-1 signaling; proteostasis

DOI:  https://doi.org/10.1016/j.celrep.2021.109623
Elife. 2021 Sep 03. pii: e65644. [Epub ahead of print]10

Neuronal regulated ire-1-dependent mRNA decay controls germline differentiation in Caenorhabditis elegans.

Mor Levi-Ferber, Rewayd Shalash, Adrien Le-Thomas, Yehuda Salzberg, Maor Shurgi, Jennifer Ic Benichou, Avi Ashkenazi, Sivan Henis-Korenblit.

  Understanding the molecular events that regulate cell pluripotency versus acquisition of differentiated somatic cell fate is fundamentally important. Studies in Caenorhabditis elegans demonstrate that knockout of the germline-specific translation repressor gld-1 causes germ cells within tumorous gonads to form germline-derived teratoma. Previously we demonstrated that endoplasmic reticulum (ER) stress enhances this phenotype to suppress germline tumor progression(Levi-Ferber et al., 2015). Here, we identify a neuronal circuit that non-autonomously suppresses germline differentiation and show that it communicates with the gonad via the neurotransmitter serotonin to limit somatic differentiation of the tumorous germline. ER stress controls this circuit through regulated inositol requiring enzyme-1 (IRE-1)-dependent mRNA decay of transcripts encoding the neuropeptide FLP-6. Depletion of FLP-6 disrupts the circuit's integrity and hence its ability to prevent somatic-fate acquisition by germline tumor cells. Our findings reveal mechanistically how ER stress enhances ectopic germline differentiation and demonstrate that regulated Ire1-dependent decay can affect animal physiology by controlling a specific neuronal circuit.

Keywords:  C. elegans; ER stress; IRE1; RIDD; cell biology; developmental biology; germline; neuronal circuit; pluripotency; teratoma

DOI:  https://doi.org/10.7554/eLife.65644
Galen Med J. 2020 ;9 e1681

Tau Abnormalities and Autophagic Defects in Neurodegenerative Disorders; A Feed-forward Cycle.

Nastaran Samimi, Akiko Asada, Kanae Ando.

  Abnormal deposition of misfolded proteins is a neuropathological characteristic shared by many neurodegenerative disorders including Alzheimer's disease (AD). Generation of excessive amounts of aggregated proteins and impairment of degradation systems for misfolded proteins such as autophagy can lead to accumulation of proteins in diseased neurons. Molecules that contribute to both these effects are emerging as critical players in disease pathogenesis. Furthermore, impairment of autophagy under disease conditions can be both a cause and a consequence of abnormal protein accumulation. Specifically, disease-causing proteins can impair autophagy, which further enhances the accumulation of abnormal proteins. In this short review, we focus on the relationship between the microtubule-associated protein tau and autophagy to highlight a feed-forward mechanism in disease pathogenesis.

Keywords:  Autophagy; Microtubule Binding Protein; Neurodegenerative Diseases; Phosphorylation; Tau; Tauopathy; Vesicle Trafficking

DOI:  https://doi.org/10.31661/gmj.v9i0.1681
Br Poult Sci. 2021 Sep 03.

Acute heat stress alters the expression of genes and proteins associated with the unfolded protein response pathway in the liver of broilers.

Q X Miao, X Y Si, Y J Xie, L Chen, X F Tang, H F Zhang.

  1. The aim of this study was to explore the effects of acute heat stress on serum hormone levels and the expression of genes and proteins related to the unfolded protein response (UPR) pathway and apoptotic process in the liver of broilers.2. A total of 144 Arbor Acres broilers (35-day-old) were randomly allocated to four different environmental-controlled chambers for acute heat exposure. The temperature of the four environmental chambers was adjusted to 26℃ (control), 29℃, 32℃, and 35℃ within one hour, respectively. The blood and liver samples were collected after six hours of constant heat exposure at set temperatures.3. The results showed that six hours of acute heat stress increased serum hormone levels and up-regulated the expression of heat shock protein. The endoplasmic reticulum (ER) stress markers, GRP78 and GRP94 in the liver of broilers were significantly upregulated at the mRNA and protein levels. The PERK, IRE1, and XBP1 genes, which are involved in the unfolded protein response signalling, were significantly up-regulated at the mRNA levels. However, other pro-apoptotic genes showed no significant changes in the liver of broiler chickens in all groups except for upregulation of the anti-apoptotic gene BCL-xl.4. The results suggested that broilers have tolerance to acute heat stress to a certain extent. The UPR activation can alleviate ER stress and further prevent apoptosis in the liver of broilers under short-term exposure to high ambient temperatures.

Keywords:  acute heat stress; apoptosis; broiler; endoplasmic reticulum; hormone; unfolded protein response

DOI:  https://doi.org/10.1080/00071668.2021.1969644
FEBS J. 2021 Sep 03.

Interplay between mammalian heat shock factors 1 and 2 in physiology and pathology.

Pia Roos-Mattjus, Lea Sistonen.

  The heat shock factors (HSFs) belong to an evolutionary conserved family of transcription factors that were discovered already over 30 years ago. The HSFs have been shown to a have a broad repertoire of target genes, and they also have crucial functions during normal development. Importantly, HSFs have been linked to several disease states, such as neurodegenerative disorders and cancer, highlighting their importance in physiology and pathology. However, it is still unclear how HSFs are regulated and how they choose their specific target genes under different conditions. Posttranslational modifications and interplay among the HSF family members have been shown to be key regulatory mechanisms for these transcription factors. In this review, we focus on the mammalian HSF1 and HSF2, including their interplay, and provide an updated overview of the advances in understanding how HSFs are regulated and how they function in multiple processes of development, aging and disease. We also discuss HSFs as therapeutic targets, especially the recently reported HSF1 inhibitors.

Keywords:  Aging; cancer; heat shock factor; neurodegeneration; transcription

DOI:  https://doi.org/10.1111/febs.16178
Sci Rep. 2021 Sep 02. 11(1): 17557

Protein disulphide isomerase (PDI) is protective against amyotrophic lateral sclerosis (ALS)-related mutant Fused in Sarcoma (FUS) in in vitro models.

S Parakh, E R Perri, M Vidal, J Sultana, S Shadfar, P Mehta, A Konopka, C J Thomas, D M Spencer, J D Atkin.

Mutations in Fused in Sarcoma (FUS) are present in familial and sporadic cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). FUS is localised in the nucleus where it has important functions in DNA repair. However, in ALS/FTD, mutant FUS mislocalises from the nucleus to the cytoplasm where it forms inclusions, a key pathological hallmark of neurodegeneration. Mutant FUS also inhibits protein import into the nucleus, resulting in defects in nucleocytoplasmic transport. Fragmentation of the neuronal Golgi apparatus, induction of endoplasmic reticulum (ER) stress, and inhibition of ER-Golgi trafficking are also associated with mutant FUS misfolding in ALS. Protein disulphide isomerase (PDI) is an ER chaperone previously shown to be protective against misfolding associated with mutant superoxide dismutase 1 (SOD1) and TAR DNA-binding protein-43 (TDP-43) in cellular and zebrafish models. However, a protective role against mutant FUS in ALS has not been previously described. In this study, we demonstrate that PDI is protective against mutant FUS. In neuronal cell line and primary cultures, PDI restores defects in nuclear import, prevents the formation of mutant FUS inclusions, inhibits Golgi fragmentation, ER stress, ER-Golgi transport defects, and apoptosis. These findings imply that PDI is a new therapeutic target in FUS-associated ALS.

DOI: https://doi.org/10.1038/s41598-021-96181-2
Elife. 2021 09 01. pii: e63453. [Epub ahead of print]10

The mitochondrial permeability transition pore activates the mitochondrial unfolded protein response and promotes aging.

Suzanne Angeli, Anna Foulger, Manish Chamoli, Tanuja Harshani Peiris, Akos Gerencser, Azar Asadi Shahmirzadi, Julie Andersen, Gordon Lithgow.

  Mitochondrial activity determines aging rate and the onset of chronic diseases. The mitochondrial permeability transition pore (mPTP) is a pathological pore in the inner mitochondrial membrane thought to be composed of the F-ATP synthase (complex V). OSCP, a subunit of F-ATP synthase, helps protect against mPTP formation. How the destabilization of OSCP may contribute to aging, however, is unclear. We have found that loss OSCP in the nematode Caenorhabditis elegans initiates the mPTP and shortens lifespan specifically during adulthood, in part via initiation of the mitochondrial unfolded protein response (UPRmt). Pharmacological or genetic inhibition of the mPTP inhibits the UPRmt and restores normal lifespan. Loss of the putative pore-forming component of F-ATP synthase extends adult lifespan, suggesting that the mPTP normally promotes aging. Our findings reveal how an mPTP/UPRmt nexus may contribute to aging and age-related diseases and how inhibition of the UPRmt may be protective under certain conditions.

Keywords:  C. elegans; F-ATP synthase; aging; c-subunit; cell biology; mitochondrial permeability transition pore; mitochondrial unfolded protein response; oscp/atp-3

DOI:  https://doi.org/10.7554/eLife.63453
FASEB J. 2021 Oct;35(10): e21894

Neuromyelitis optica (NMO)-IgG-driven organelle reorganization in human iPSC-derived astrocytes.

Sukhee Cho, Hyein Lee, Minkyo Jung, Kirim Hong, Seung-Hwa Woo, Young-Sam Lee, Byoung Joon Kim, Mi Young Jeon, Jinsoo Seo, Ji Young Mun.

  Neuromyelitis optica (NMO) is an autoimmune disease that primarily targets astrocytes. Autoantibodies (NMO-IgG) against the water channel protein, aquaporin 4 (AQP4), are a serologic marker in NMO patients, and they are known to be responsible for the pathophysiology of the disease. In the brain, AQP4 is mainly expressed in astrocytes, especially at the end-feet, where they form the blood-brain barrier. Following the interaction between NMO-IgG and AQP4 in astrocytes, rapid AQP4 endocytosis initiates pathogenesis. However, the cellular and molecular mechanisms of astrocyte destruction by autoantibodies remain largely elusive. We established an in vitro human astrocyte model system using induced pluripotent stem cells (iPSCs) technology in combination with NMO patient-derived serum and IgG to elucidate the cellular and functional changes caused by NMO-IgG. Herein, we observed that NMO-IgG induces structural alterations in mitochondria and their association with the endoplasmic reticulum (ER) and lysosomes at the ultrastructural level, which potentially leads to impaired mitochondrial functions and dynamics. Indeed, human astrocytes display impaired mitochondrial bioenergetics and autophagy activity in the presence of NMO-IgG. We further demonstrated NMO-IgG-driven ER membrane deformation into a multilamellar structure in human astrocytes. Together, we show that NMO-IgG rearranges cellular organelles and alter their functions and that our in vitro system using human iPSCs offers previously unavailable experimental opportunities to study the pathophysiological mechanisms of NMO in human astrocytes or conduct large-scale screening for potential therapeutic compounds targeting astrocytic abnormalities in patients with NMO.

Keywords:  astrocytes; autophagy; endoplasmic reticulum; human iPSC; lysosome; metabolic flux; mitochondria; neuromyelitis optica (NMO)

DOI:  https://doi.org/10.1096/fj.202100637R
EMBO J. 2021 Aug 30. e108863

Autophagy in major human diseases.

Daniel J Klionsky, Giulia Petroni, Ravi K Amaravadi, Eric H Baehrecke, Andrea Ballabio, Patricia Boya, José Manuel Bravo-San Pedro, Ken Cadwell, Francesco Cecconi, Augustine M K Choi, Mary E Choi, Charleen T Chu, Patrice Codogno, Maria Isabel Colombo, Ana Maria Cuervo, Vojo Deretic, Ivan Dikic, Zvulun Elazar, Eeva-Liisa Eskelinen, Gian Maria Fimia, David A Gewirtz, Douglas R Green, Malene Hansen, Marja Jäättelä, Terje Johansen, Gábor Juhász, Vassiliki Karantza, Claudine Kraft, Guido Kroemer, Nicholas T Ktistakis, Sharad Kumar, Carlos Lopez-Otin, Kay F Macleod, Frank Madeo, Jennifer Martinez, Alicia Meléndez, Noboru Mizushima, Christian Münz, Josef M Penninger, Rushika M Perera, Mauro Piacentini, Fulvio Reggiori, David C Rubinsztein, Kevin M Ryan, Junichi Sadoshima, Laura Santambrogio, Luca Scorrano, Hans-Uwe Simon, Anna Katharina Simon, Anne Simonsen, Alexandra Stolz, Nektarios Tavernarakis, Sharon A Tooze, Tamotsu Yoshimori, Junying Yuan, Zhenyu Yue, Qing Zhong, Lorenzo Galluzzi, Federico Pietrocola.

  Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.

Keywords:  aging; cancer; inflammation; metabolic syndromes; neurodegeneration

DOI:  https://doi.org/10.15252/embj.2021108863
Nat Commun. 2021 Sep 01. 12(1): 5220

Improved modeling of human AD with an automated culturing platform for iPSC neurons, astrocytes and microglia.

Reina Bassil, Kenneth Shields, Kevin Granger, Ivan Zein, Shirley Ng, Ben Chih.

Advancement in human induced pluripotent stem cell (iPSC) neuron and microglial differentiation protocols allow for disease modeling using physiologically relevant cells. However, iPSC differentiation and culturing protocols have posed challenges to maintaining consistency. Here, we generated an automated, consistent, and long-term culturing platform of human iPSC neurons, astrocytes, and microglia. Using this platform we generated a iPSC AD model using human derived cells, which showed signs of Aβ plaques, dystrophic neurites around plaques, synapse loss, dendrite retraction, axon fragmentation, phospho-Tau induction, and neuronal cell death in one model. We showed that the human iPSC microglia internalized and compacted Aβ to generate and surround the plaques, thereby conferring some neuroprotection. We investigated the mechanism of action of anti-Aβ antibodies protection and found that they protected neurons from these pathologies and were most effective before pTau induction. Taken together, these results suggest that this model can facilitate target discovery and drug development efforts.

DOI: https://doi.org/10.1038/s41467-021-25344-6
Elife. 2021 Sep 01. pii: e71642. [Epub ahead of print]10

Endoplasmic reticulum tubules limit the size of misfolded protein condensates.

Smriti Parashar, Ravi Chidambaram, Shuliang Chen, Christina R Liem, Eric Griffis, Gerard G Lambert, Nathan C Shaner, Matthew Wortham, Jesse C Hay, Susan Ferro-Novick.

  The endoplasmic reticulum (ER) is composed of sheets and tubules. Here we report that the COPII coat subunit, SEC24C, works with the long form of the tubular ER-phagy receptor, RTN3, to target dominant-interfering mutant proinsulin Akita puncta to lysosomes. When the delivery of Akita puncta to lysosomes was disrupted, large puncta accumulated in the ER. Unexpectedly, photobleach analysis indicated that Akita puncta behaved as condensates and not aggregates, as previously suggested. Akita puncta enlarged when either RTN3 or SEC24C were depleted, or when ER sheets were proliferated by either knocking out Lunapark or overexpressing CLIMP63. Other ER-phagy substrates that are segregated into tubules behaved like Akita, while a substrate (type I procollagen) that is degraded by the ER-phagy sheets receptor, FAM134B, did not. Conversely, when ER tubules were augmented in Lunapark knock-out cells by overexpressing reticulons, ER-phagy increased and the number of large Akita puncta were reduced. Our findings imply that segregating cargos into tubules has two beneficial roles. First, it localizes mutant misfolded proteins, the receptor and SEC24C to the same ER domain. Second, physically restraining condensates within tubules, before they undergo ER-phagy, prevents them from enlarging and impacting cell health.

Keywords:  cell biology

DOI:  https://doi.org/10.7554/eLife.71642
Mol Neurodegener. 2021 Aug 28. 16(1): 59

Extracellular protein components of amyloid plaques and their roles in Alzheimer's disease pathology.

M Mahafuzur Rahman, Christofer Lendel.

  Alzheimer's disease (AD) is pathologically defined by the presence of fibrillar amyloid β (Aβ) peptide in extracellular senile plaques and tau filaments in intracellular neurofibrillary tangles. Extensive research has focused on understanding the assembly mechanisms and neurotoxic effects of Aβ during the last decades but still we only have a brief understanding of the disease associated biological processes. This review highlights the many other constituents that, beside Aβ, are accumulated in the plaques, with the focus on extracellular proteins. All living organisms rely on a delicate network of protein functionality. Deposition of significant amounts of certain proteins in insoluble inclusions will unquestionably lead to disturbances in the network, which may contribute to AD and copathology. This paper provide a comprehensive overview of extracellular proteins that have been shown to interact with Aβ and a discussion of their potential roles in AD pathology. Methods that can expand the knowledge about how the proteins are incorporated in plaques are described. Top-down methods to analyze post-mortem tissue and bottom-up approaches with the potential to provide molecular insights on the organization of plaque-like particles are compared. Finally, a network analysis of Aβ-interacting partners with enriched functional and structural key words is presented.

Keywords:  Alzheimer’s disease; Amyloid corona; Amyloid-β; Protein interaction network; Senile plaque

DOI:  https://doi.org/10.1186/s13024-021-00465-0
Nat Commun. 2021 Sep 02. 12(1): 5242

Functional characterization of T2D-associated SNP effects on baseline and ER stress-responsive β cell transcriptional activation.

Shubham Khetan, Susan Kales, Romy Kursawe, Alexandria Jillette, Jacob C Ulirsch, Steven K Reilly, Duygu Ucar, Ryan Tewhey, Michael L Stitzel.

Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) at >250 loci in the human genome to type 2 diabetes (T2D) risk. For each locus, identifying the functional variant(s) among multiple SNPs in high linkage disequilibrium is critical to understand molecular mechanisms underlying T2D genetic risk. Using massively parallel reporter assays (MPRA), we test the cis-regulatory effects of SNPs associated with T2D and altered in vivo islet chromatin accessibility in MIN6 β cells under steady state and pathophysiologic endoplasmic reticulum (ER) stress conditions. We identify 1,982/6,621 (29.9%) SNP-containing elements that activate transcription in MIN6 and 879 SNP alleles that modulate MPRA activity. Multiple T2D-associated SNPs alter the activity of short interspersed nuclear element (SINE)-containing elements that are strongly induced by ER stress. We identify 220 functional variants at 104 T2D association signals, narrowing 54 signals to a single candidate SNP. Together, this study identifies elements driving β cell steady state and ER stress-responsive transcriptional activation, nominates causal T2D SNPs, and uncovers potential roles for repetitive elements in β cell transcriptional stress response and T2D genetics.

DOI: https://doi.org/10.1038/s41467-021-25514-6
Transl Neurodegener. 2021 Sep 01. 10(1): 33

Mitochondrial links between brain aging and Alzheimer's disease.

Heather M Wilkins, Russell H Swerdlow.

  Advancing age is a major risk factor for Alzheimer's disease (AD). This raises the question of whether AD biology mechanistically diverges from aging biology or alternatively represents exaggerated aging. Correlative and modeling studies can inform this question, but without a firm grasp of what drives aging and AD it is difficult to definitively resolve this quandary. This review speculates over the relevance of a particular hallmark of aging, mitochondrial function, to AD, and further provides background information that is pertinent to and provides perspective on this speculation.

Keywords:  Aging; Alzheimer’s disease; Mitochondria; Mitochondrial DNA

DOI:  https://doi.org/10.1186/s40035-021-00261-2
Cell Rep. 2021 Aug 31. pii: S2211-1247(21)01081-0. [Epub ahead of print]36(9): 109638

Long-term depression links amyloid-β to the pathological hyperphosphorylation of tau.

Henry B C Taylor, Nigel J Emptage, Alexander F Jeans.

  In Alzheimer's disease, soluble oligomers of the amyloid-β peptide (Aβo) trigger a cascade of events that includes abnormal hyperphosphorylation of the protein tau, which is essential for pathogenesis. However, the mechanistic link between these two key pathological proteins remains unclear. Using hippocampal slices, we show here that an Aβo-mediated increase in glutamate release probability causes enhancement of synaptically evoked N-methyl-d-aspartate subtype glutamate receptor (NMDAR)-dependent long-term depression (LTD). We also find that elevated glutamate release probability is required for Aβo-induced pathological hyperphosphorylation of tau, which is likewise NMDAR dependent. Finally, we show that chronic, repeated chemical or optogenetic induction of NMDAR-dependent LTD alone is sufficient to cause tau hyperphosphorylation without Aβo. Together, these results support a possible causal chain in which Aβo increases glutamate release probability, thus leading to enhanced LTD induction, which in turn drives hyperphosphorylation of tau. Our data identify a mechanistic pathway linking the two critical pathogenic proteins of AD.

Keywords:  Alzheimer’s disease; amyloid-β; long-term depression; neurotransmitter release; phosphorylation; tau

DOI:  https://doi.org/10.1016/j.celrep.2021.109638
Cell Rep. 2021 Aug 31. pii: S2211-1247(21)01079-2. [Epub ahead of print]36(9): 109636

Patient-specific iPSCs carrying an SFTPC mutation reveal the intrinsic alveolar epithelial dysfunction at the inception of interstitial lung disease.

Konstantinos-Dionysios Alysandratos, Scott J Russo, Anton Petcherski, Evan P Taddeo, Rebeca Acín-Pérez, Carlos Villacorta-Martin, J C Jean, Surafel Mulugeta, Luis R Rodriguez, Benjamin C Blum, Ryan M Hekman, Olivia T Hix, Kasey Minakin, Marall Vedaie, Seunghyi Kook, Andrew M Tilston-Lunel, Xaralabos Varelas, Jennifer A Wambach, F Sessions Cole, Aaron Hamvas, Lisa R Young, Marc Liesa, Andrew Emili, Susan H Guttentag, Orian S Shirihai, Michael F Beers, Darrell N Kotton.

  Alveolar epithelial type 2 cell (AEC2) dysfunction is implicated in the pathogenesis of adult and pediatric interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF); however, identification of disease-initiating mechanisms has been impeded by inability to access primary AEC2s early on. Here, we present a human in vitro model permitting investigation of epithelial-intrinsic events culminating in AEC2 dysfunction, using patient-specific induced pluripotent stem cells (iPSCs) carrying an AEC2-exclusive disease-associated variant (SFTPCI73T). Comparing syngeneic mutant versus gene-corrected iPSCs after differentiation into AEC2s (iAEC2s), we find that mutant iAEC2s accumulate large amounts of misprocessed and mistrafficked pro-SFTPC protein, similar to in vivo changes, resulting in diminished AEC2 progenitor capacity, perturbed proteostasis, altered bioenergetic programs, time-dependent metabolic reprogramming, and nuclear factor κB (NF-κB) pathway activation. Treatment of SFTPCI73T-expressing iAEC2s with hydroxychloroquine, a medication used in pediatric ILD, aggravates the observed perturbations. Thus, iAEC2s provide a patient-specific preclinical platform for modeling the epithelial-intrinsic dysfunction at ILD inception.

Keywords:  NF-κB; autophagy; bioenergetics; iPSC-derived alveolar epithelial type 2 cells; idiopathic pulmonary fibrosis; induced pluripotent stem cells; interstitial lung disease; metabolic reprogramming; proteostasis; surfactant protein C

DOI:  https://doi.org/10.1016/j.celrep.2021.109636
ACS Chem Neurosci. 2021 Sep 02.

A Comprehensive Insight into the Mechanisms of Dopamine in Disrupting Aβ Protofibrils and Inhibiting Aβ Aggregation.

Yujie Chen, Xuhua Li, Chendi Zhan, Zenghui Lao, Fangying Li, Xuewei Dong, Guanghong Wei.

  Fibrillary aggregates of amyloid-β (Aβ) are the pathological hallmark of Alzheimer's disease (AD). Clearing Aβ deposition or inhibiting Aβ aggregation is a promising approach to treat AD. Experimental studies reported that dopamine (DA), an important neurotransmitter, can inhibit Aβ aggregation and disrupt Aβ fibrils in a dose-dependent manner. However, the underlying molecular mechanisms still remain mostly elusive. Herein, we investigated the effect of DA on Aβ42 protofibrils at three different DA-to-Aβ molar ratios (1:1, 2:1, and 10:1) using all-atom molecular dynamics simulations. Our simulations demonstrate that protonated DA at a DA-to-Aβ ratio of 2:1 exhibits stronger Aβ protofibril disruptive capacity than that at a molar-ratio of 1:1 by mostly disrupting the F4-L34-V36 hydrophobic core. When the ratio of DA-to-Aβ increases to 10:1, DA has a high probability to bind to the outer surface of protofibril and has negligible effect on the protofibril structure. Interestingly, at the same DA-to-Aβ ratio (10:1), a mixture of protonated (DA+) and deprotonated (DA0) DA molecules significantly disrupts Aβ protofibrils by the binding of DA0 to the F4-L34-V36 hydrophobic core. Replica-exchange molecular dynamics simulations of Aβ42 dimer show that DA+ inhibits the formation of β-sheets, K28-A42/K28-D23 salt-bridges, and interpeptide hydrophobic interactions and results in disordered coil-rich Aβ dimers, which would inhibit the subsequent fibrillization of Aβ. Further analyses reveal that DA disrupts Aβ protofibril and prevents Aβ dimerization mostly through π-π stacking interactions with residues F4, H6, and H13, hydrogen bonding interactions with negatively charged residues D7, E11, E22 and D23, and cation-π interactions with residues R5. This study provides a complete picture of the molecular mechanisms of DA in disrupting Aβ protofibril and inhibiting Aβ aggregation, which could be helpful for the design of potent drug candidates for the treatment/intervention of AD.

Keywords:  Amyloid-β; disruptive mechanism; dopamine; inhibitory mechanism; molecular dynamics simulation; protofibril

DOI:  https://doi.org/10.1021/acschemneuro.1c00306
Wiley Interdiscip Rev RNA. 2021 Aug 31. e1689

A (dis)integrated stress response: Genetic diseases of eIF2α regulators.

Alyssa M English, Katelyn M Green, Stephanie L Moon.

  The integrated stress response (ISR) is a conserved mechanism by which eukaryotic cells remodel gene expression to adapt to intrinsic and extrinsic stressors rapidly and reversibly. The ISR is initiated when stress-activated protein kinases phosphorylate the major translation initiation factor eukaryotic translation initiation factor 2ɑ (eIF2ɑ), which globally suppresses translation initiation activity and permits the selective translation of stress-induced genes including important transcription factors such as activating transcription factor 4 (ATF4). Translationally repressed messenger RNAs (mRNAs) and noncoding RNAs assemble into cytoplasmic RNA-protein granules and polyadenylated RNAs are concomitantly stabilized. Thus, regulated changes in mRNA translation, stability, and localization to RNA-protein granules contribute to the reprogramming of gene expression that defines the ISR. We discuss fundamental mechanisms of RNA regulation during the ISR and provide an overview of a growing class of genetic disorders associated with mutant alleles of key translation factors in the ISR pathway. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease Translation > Translation Regulation RNA in Disease and Development > RNA in Development.

Keywords:  RNA-protein granules; eIF2α; genetic diseases; integrated stress response; translation

DOI:  https://doi.org/10.1002/wrna.1689
Biochimie. 2021 Aug 31. pii: S0300-9084(21)00200-5. [Epub ahead of print]

A mass spectrometric approach to study the interaction of amyloid β peptides with human α-2-macroglobulin.

Aleksandr Viktorovich Protasov, Olga Alexandrovna Mirgorodskaya, Yuri Petrovich Kozmin, Johan Gobom.

  We used MALDI-MS to study the interaction of amyloid β (Aβ) peptides with alpha-2-macroglobulin (α2M). The binding of amyloid beta (Aβ) peptides to alpha-2-macroglobulin (α2M) was found to inhibit the ability of trypsin to cleave out the peptide α2M 705-715 (Pep-α2M) from α2M. This was observed with both purified α2M and α2M in human serum. We found that Aβ 1-38, Aβ1-40, and Aβ 1-42, all inhibit the interaction of α2M with trypsin, with inhibition rate independent of the length of the Aβ peptide. Further, we show that for complete inhibition, two peptide molecules must be attached to one α2M molecule; one for each of its two subunits. A region was revealed within the Aβ sequence, in which proteolytic cleavage (Lys-28) and oxidation (Met-35) lead to a loss of their ability to inhibit the interaction of trypsin with α2M. Furthermore, we show that after the formation of a trypsin complex with α2M and cleavage of α2M to produce the α2M 705-715, Aβ peptides continue to bind to the protein in the same proportions. However, Aβ peptides treated with DMSO lost their ability to bind to α2M and thereby to inhibit the interaction of trypsin with α2M. While maintaining their primary structure, such an effect can be explained only by conformational changes in the peptides, suggesting the possibility to use our analytical approach to distinguish between conformational isomers of Aβ peptides.

Keywords:  Alpha-2-macroglobulin; Alzheimer's disease; Amyloid beta; Biomarker

DOI:  https://doi.org/10.1016/j.biochi.2021.08.008
Cell Signal. 2021 Aug 27. pii: S0898-6568(21)00227-8. [Epub ahead of print] 110138

Decreased autophagy impairs osteogenic differentiation of adipose-derived stem cells via Notch signaling in diabetic osteoporosis mice.

Pengcheng Rao, Fangzhi Lou, Daowen Luo, Chenglong Huang, Kui Huang, Zhihao Yao, Jingang Xiao.

  BACKGROUND: The osteogenic differentiation ability of adipose-derived stem cells (ASCs) is attenuated in type 2 diabetic osteoporosis (Dop) mice. Several studies suggest autophagy and Notch signaling pathway play vital roles in cell proliferation, differentiation, and osteogenesis. However, the mechanisms of autophagy and Notch signaling in the osteogenic differentiation of Dop ASCs were unclear. Thus, it is meaningful to reveal potential correlations between autophagy, Notch signaling, and osteogenesis, and explore involved molecular mechanisms in Dop ASCs.MATERIALS AND METHODS: The diabetic osteoporosis C57BL/6 mouse model, which was confirmed by micro-CT and HE & Masson staining, was established through high-sugar and high-fat diet and streptozotocin injection. ASCs were obtained from the inguinal subcutaneous fat of Dop mice. The multi-differentiation potential of ASCs was evaluated by staining with Alizarin Red (osteogenesis), Oil Red O (adipogenesis), and Alcian blue (chondrogenesis). Cell viability was assessed by Cell Counting Kit-8 assay. Torin1, an inhibitor of mTOR, was used to stimulate the autophagy signaling pathway. DAPT, a γ-secretase inhibitor, was used to suppress Notch signaling pathway activity. Gene and protein expression of autophagy, Notch signaling pathway, and osteogenic factors were detected by real-time quantitative PCR, western blot, and immunofluorescence microscopy.
RESULTS: Our findings showed autophagy and osteogenic differentiation ability of Dop ASCs exhibited downward trends that were both rescued by Torin1. Notch signaling was suppressed in Dop ASCs, but upregulated when autophagy was activated. After activation of autophagy, DAPT treatment led to decreased Notch signaling pathway activation and attenuated osteogenic differentiation ability in Dop ASCs.
CONCLUSIONS: Downregulated autophagy suppressed Notch signaling, leading to a reduced osteogenic differentiation capacity of Dop ASCs, and Torin1 can rescue this process by activating autophagy. Our findings contribute to understanding the mechanism underlying impairment of the osteogenic differentiation ability of Dop ASCs.

Keywords:  Adipose-derived stem cells; Autophagy; Diabetic osteoporosis; Notch signaling pathway; Osteogenic differentiation

DOI:  https://doi.org/10.1016/j.cellsig.2021.110138
Geroscience. 2021 Aug 31.

Einstein-Nathan Shock Center: translating the hallmarks of aging to extend human health span.

Ana Maria Cuervo, Derek M Huffman, Jan Vijg, Sofiya Milman, Rajat Singh, Nir Barzilai.

  The overarching mission of the Einstein-Nathan Shock Center (E-NSC) is to make scientific discoveries in geroscience, leveraging on the expertise in our center in 6 out of the 7 pillars of aging, and to translate their effects towards drug discovery. The relevance of this basic biology of aging discoveries to humans will be confirmed through the unique gero-human resource at E-NSC. This is achieved through services provided by E-NSC, connectivity among its members, attracting worldwide investigators, and providing them with the opportunities to become future leaders. The two central components of the E-NSC are (a) cutting-edge research programs and (b) unique E-NSC research support cores. E-NSC scientists lead NIH-supported cutting-edge research programs that integrate key hallmarks of aging including proteostasis/autophagy, metabolism/inflammaging, genetic/epigenetics, stem cells/regeneration, and translational aging/longevity. Since the inception of the E-NSC, the well-integrated, collaborative, and innovative nature of the multiple supporting state-of-the-art E-NSC research cores form the bedrock of research success at the E-NSC. The three state-of-the-art E-NSC research cores, (i) Proteostasis of Aging Core (PAC), (ii) the Health Span Core (HSC), and (iii) the Human Multi-Omics Core (HMOC), have allowed impressive expansion of translational biological research programs. Expansion was facilitated through the wealth of data coming from genomics/proteomics and metabolomic analysis on human longevity studies, due to access to a variety of biological samples from elderly subjects in clinical trials with aging-targeting drugs, and new drug design services via the PAC to target the hallmarks of aging.

Keywords:  Autophagy; Genomics; Health span; Metabolism; Parabiosis; Proteomics; Proteostasis

DOI:  https://doi.org/10.1007/s11357-021-00428-9
Mol Med Rep. 2021 Nov;pii: 746. [Epub ahead of print]24(5):

Involvement of autophagy in diosgenin‑induced megakaryocyte differentiation in human erythroleukemia cells.

Dima Diab, Aline Pinon, Catherine Ouk, Rouba Hage-Sleiman, Mona Diab-Assaf, Bertrand Liagre, David Yannick Leger.

  Natural agents have been used to restart the process of differentiation that is inhibited during leukemic transformation of hematopoietic stem or progenitor cells. Autophagy is a housekeeping pathway that maintains cell homeostasis against stress by recycling macromolecules and organelles and plays an important role in cell differentiation. In the present study, an experimental model was established to investigate the involvement of autophagy in the megakaryocyte differentiation of human erythroleukemia (HEL) cells induced by diosgenin [also known as (25R)‑Spirosten‑5‑en‑3b‑ol]. It was demonstrated that Atg7 expression was upregulated from day 1 of diosgenin‑induced differentiation and was accompanied by a significant elevation in the conversion of light chain 3 A/B (LC3‑A/B)‑I to LC3‑A/B‑II. Autophagy was modulated before or after the induction of megakaryocyte differentiation using 3‑methyladenine (3‑MA, autophagy inhibitor) and metformin (Met, autophagy initiation activator). 3‑MA induced a significant accumulation of the LC3 A/B‑II form at day 8 of differentiation. It was revealed that 3‑MA had a significant repressive effect on the nuclear (polyploidization) and membrane glycoprotein V [(GpV) expression] maturation. On the other hand, autophagy activation increased GpV genomic expression, but did not change the nuclear maturation profile after HEL cells treatment with Met. It was concluded that autophagy inhibition had a more prominent effect on the diosgenin‑differentiated cells than autophagy activation.

Keywords:  3‑methyladenine; autophagy; diosgenin; human erythroleukemia cells; megakaryocyte differentiation

DOI:  https://doi.org/10.3892/mmr.2021.12386
RSC Chem Biol. 2021 Apr 01. 2(2): 636-644

Protein degradation profile reveals dynamic nature of 20S proteasome small molecule stimulation.

Rachel A Coleman, Rodrigo Mohallem, Uma K Aryal, Darci J Trader.

Small molecules have been discovered to stimulate the 20S core particle (CP) of the proteasome to degrade proteins. However, the impact a 20S CP stimulator can have on the regulation of protein levels has not been fully characterized. Previous studies have focused on using one kind of stimulator to enhance the degradation of specific 20S CP substrates. We present here a study that utilizes several 20S CP stimulators to determine how each can affect the degradation of proteins in a biochemical assay with purified proteins and of an overexpressed GFP-fusion protein in cells. We also evaluate the effects of two stimulators on the whole cellular proteome in HEK-293T cells using label-free quantitative proteomic analysis for a broader understanding on their impact. Our studies demonstrate that 20S CP stimulation is likely to promote the degradation of significantly disordered proteins; however, the specific effect on the regulation of protein levels appears to be dependent on the mechanism of action of each stimulator due to the dynamic nature of the 20S CP. Our results reveal the potential of tailoring small molecule stimulators to influence the degradation of certain protein types and 20S CP substrates.

DOI: https://doi.org/10.1039/d0cb00191k