bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2022‒12‒04
fourteen papers selected by
Rich Giadone
Harvard University
  1. Proteostasis in aging-associated ocular disease.
  2. Neuronal IRE-1 coordinates an organism-wide cold stress response by regulating fat metabolism.
  3. Protein painting reveals pervasive remodeling of conserved proteostasis machinery in response to pharmacological stimuli.
  4. A pathological role of the Hsp40 protein Ydj1/DnaJA1 in models of Alzheimer's disease.
  5. The regulatory role of endoplasmic reticulum chaperone proteins in neurodevelopment.
  6. Direct observation of Hsp90-induced compaction in a protein chain.
  7. Secretome of young mesenchymal stromal cells rejuvenates aged mesenchymal stromal cells by normalizing their phenotype and restoring their differentiation profile.
  8. Greater genetic diversity is needed in human pluripotent stem cell models.
  9. A reference human induced pluripotent stem cell line for large-scale collaborative studies.
  10. Increased post-mitotic senescence in aged human neurons is a pathological feature of Alzheimer's disease.
  11. Early diagnosis and treatment of Alzheimer's disease by targeting toxic soluble Aβ oligomers.
  12. Signal sequences encode information for protein folding in the endoplasmic reticulum.
  13. Beneficial Effect of a Small Pharmacologic Chaperone on the Established Alzheimer's Disease Phenotype.
  14. Autophagic reprogramming of bone marrow-derived macrophages.
  1. Mol Aspects Med. 2022 Nov 29. pii: S0098-2997(22)00102-9. [Epub ahead of print]88 101157
    Proteostasis in aging-associated ocular disease.
    Jasper Weinberg, Mohita Gaur, Anand Swaroop, Allen Taylor.
      Vision impairment has devastating consequences for the quality of human life. The cells and tissues associated with the visual process must function throughout one's life span and maintain homeostasis despite exposure to a variety of insults. Maintenance of the proteome is termed proteostasis, and is vital for normal cellular functions, especially at an advanced age. Here we describe basic aspects of proteostasis, from protein synthesis and folding to degradation, and discuss the current status of the field with a particular focus on major age-related eye diseases: age-related macular degeneration, cataract, and glaucoma. Our intent is to allow vision scientists to determine where and how to harness the proteostatic machinery for extending functional homeostasis in the aging retina, lens, and trabecular meshwork. Several common themes have emerged despite these tissues having vastly different metabolisms. Continued exposure to insults, including chronic stress with advancing age, increases proteostatic burden and reduces the fidelity of the degradation machineries including the ubiquitin-proteasome and the autophagy-lysosome systems that recognize and remove damaged proteins. This "double jeopardy" results in an exponential accumulation of cytotoxic proteins with advancing age. We conclude with a discussion of the challenges in maintaining an appropriate balance of protein synthesis and degradation pathways, and suggest that harnessing proteostatic capacities should provide new opportunities to design interventions for attenuating age-related eye diseases before they limit sight.
    Keywords:  Age-related macular degeneration; Aging; Autophagy; Cataract; Development; Diabetes; Glaucoma; Lens; Nutrition; Retina; Retinopathy; Ubiquitin-proteasome system
    DOI:  https://doi.org/10.1016/j.mam.2022.101157
  2. Cell Rep. 2022 Nov 29. pii: S2211-1247(22)01617-5. [Epub ahead of print]41(9): 111739
    Neuronal IRE-1 coordinates an organism-wide cold stress response by regulating fat metabolism.
    Reut Dudkevich, Jhee Hong Koh, Caroline Beaudoin-Chabot, Cenk Celik, Ilana Lebenthal-Loinger, Sarit Karako-Lampert, Syed Ahmad-Albukhari, Guillaume Thibault, Sivan Henis-Korenblit.
      Cold affects many aspects of biology, medicine, agriculture, and industry. Here, we identify a conserved endoplasmic reticulum (ER) stress response, distinct from the canonical unfolded protein response, that maintains lipid homeostasis during extreme cold. We establish that the ER stress sensor IRE-1 is critical for resistance to extreme cold and activated by cold temperature. Specifically, neuronal IRE-1 signals through JNK-1 and neuropeptide signaling to regulate lipid composition within the animal. This cold-response pathway can be bypassed by dietary supplementation with unsaturated fatty acids. Altogether, our findings define an ER-centric conserved organism-wide cold stress response, consisting of molecular neuronal sensors, effectors, and signaling moieties, which control adaptation to cold conditions in the organism. Better understanding of the molecular basis of this stress response is crucial for the optimal use of cold conditions on live organisms and manipulation of lipid saturation homeostasis, which is perturbed in human pathologies.
    Keywords:  C. elegans; CP: Metabolism; IRE-1; IRE1; JNK; cell non-autonomous stress response; cold stress; endoplasmic reticulum; fat metabolism; lipids; unfolded protein response
    DOI:  https://doi.org/10.1016/j.celrep.2022.111739
  3. NPJ Syst Biol Appl. 2022 11 28. 8(1): 46
    Protein painting reveals pervasive remodeling of conserved proteostasis machinery in response to pharmacological stimuli.
    Dezerae Cox, Angelique R Ormsby, Gavin E Reid, Danny M Hatters.
      The correct spatio-temporal organization of the proteome is essential for cellular homeostasis. However, a detailed mechanistic understanding of this organization and how it is altered in response to external stimuli in the intact cellular environment is as-yet unrealized. 'Protein painting methods provide a means to address this gap in knowledge by monitoring the conformational status of proteins within cells at the proteome-wide scale. Here, we demonstrate the ability of a protein painting method employing tetraphenylethene maleimide (TPE-MI) to reveal proteome network remodeling in whole cells in response to a cohort of commonly used pharmacological stimuli of varying specificity. We report specific, albeit heterogeneous, responses to individual stimuli that coalesce on a conserved set of core cellular machineries. This work expands our understanding of proteome conformational remodeling in response to cellular stimuli, and provides a blueprint for assessing how these conformational changes may contribute to disorders characterized by proteostasis imbalance.
    DOI:  https://doi.org/10.1038/s41540-022-00256-3
  4. Cell Stress. 2022 May;6(5): 61-64
    A pathological role of the Hsp40 protein Ydj1/DnaJA1 in models of Alzheimer's disease.
    Jelena Tadic, Julia Ring, Andrea Jerkovic, Selena Ristic, Marta Maglione, Jörn Dengjel, Stephan J Sigrist, Tobias Eisenberg.
      Alzheimer's disease (AD) is the most common form of dementia with millions of people affected worldwide. Pathophysiological manifestations of AD include the extracellular accumulation of amyloid beta (Abeta) pep-tides, products of the proteolytic cleavage of the amy-loid precursor protein APP. Increasing evidence sug-gests that Abeta peptides also accumulate intracellular-ly, triggering neurotoxic events such as mitochondrial dysfunction. However, the molecular factors driving formation and toxicity of intracellular Abeta are poorly understood. In our recent study [EMBO Mol Med 2022 - e13952], we used different eukaryotic model systems to identify such factors. Based on a genetic screen in yeast and subsequent molecular analyses, we found that both the yeast chaperone Ydj1 and its human ortholog DnaJA1 physically interact with Abeta, facili-tate the aggregation of Abeta peptides into small oli-gomers and promote their translocation to mitochon-dria. Deletion or downregulation of this chaperone pro-tected from Abeta-mediated toxicity in yeast and Dro-sophila AD models, respectively. Most importantly, the identified chaperone is found to be dysregulated in post-mortem human samples of AD patients. Here, we aim to outline our key findings, highlighting pathological functions of a heat shock protein (Hsp) family member, which are generally considered protective rather than toxic during neurodegeneration. Our results thus chal-lenge the concept of developing generalized chaperone activation-based therapies and call for carefully consid-ering also maladaptive functions of specific heat shock proteins.
    Keywords:  Alzheimer’s disease; DnaJA1; Drosophila; HSP40; Ydj1; amyloid beta 42; heat shock proteins; neurodegeneration; oligomers; yeast cell death
    DOI:  https://doi.org/10.15698/cst2022.05.267
  5. Front Neurosci. 2022 ;16 1032607
    The regulatory role of endoplasmic reticulum chaperone proteins in neurodevelopment.
    Hongji Sun, Mengxue Wu, Minxin Wang, Xiaomin Zhang, Jia Zhu.
      The endoplasmic reticulum (ER) is the largest tubular reticular organelle spanning the cell. As the main site of protein synthesis, Ca2+ homeostasis maintenance and lipid metabolism, the ER plays a variety of essential roles in eukaryotic cells, with ER molecular chaperones participate in all these processes. In recent years, it has been reported that the abnormal expression of ER chaperones often leads to a variety of neurodevelopmental disorders (NDDs), including abnormal neuronal migration, neuronal morphogenesis, and synaptic function. Neuronal development is a complex and precisely regulated process. Currently, the mechanism by which neural development is regulated at the ER level remains under investigation. Therefore, in this work, we reviewed the recent advances in the roles of ER chaperones in neural development and developmental disorders caused by the deficiency of these molecular chaperones.
    Keywords:  endoplasmic reticulum; molecular chaperone; neurodevelopment; neuronal migration; neuronal morphogenesis; synaptic function
    DOI:  https://doi.org/10.3389/fnins.2022.1032607
  6. Cell Rep. 2022 Nov 29. pii: S2211-1247(22)01612-6. [Epub ahead of print]41(9): 111734
    Direct observation of Hsp90-induced compaction in a protein chain.
    Alireza Mashaghi, Fatemeh Moayed, Eline J Koers, Yang Zheng, Katharina Till, Günter Kramer, Matthias P Mayer, Sander J Tans.
      The chaperone heat shock protein 90 (Hsp90) is well known to undergo important conformational changes, which depend on nucleotide and substrate interactions. Conversely, how the conformations of its unstable and disordered substrates are affected by Hsp90 is difficult to address experimentally yet is central to its function. Here, using optical tweezers, we find that Hsp90 promotes local contractions in unfolded chains that drive their global compaction down to dimensions of folded states. This compaction has a gradual nature while showing small steps, is stimulated by ATP, and performs mechanical work against counteracting forces that expand the chain dimensions. The Hsp90 interactions suppress the formation of larger-scale folded, misfolded, and aggregated structures. The observations support a model in which Hsp90 alters client conformations directly by promoting local intra-chain interactions while suppressing distant ones. We conjecture that chain compaction may be central to how Hsp90 protects unstable clients and cooperates with Hsp70.
    Keywords:  CP: Molecular biology; HSP90; chaperone; conformational heterogeneity; optical tweezers; protein chain compaction
    DOI:  https://doi.org/10.1016/j.celrep.2022.111734
  7. Stem Cells Dev. 2022 Dec 01.
    Secretome of young mesenchymal stromal cells rejuvenates aged mesenchymal stromal cells by normalizing their phenotype and restoring their differentiation profile.
    Madhurima Das, Prajakta Teli, Anuradha Vaidya, Vaijayanti Prakash Kale.
      During aging, the proliferation and differentiation ability of mesenchymal stem/stromal cells (MSCs) gets affected, and hence, aged MSCs are not preferred for regenerative purposes. Rapid identification of aging-associated changes within MSCs and the mechanistic pathways involved is necessary to determine optimal cell sources to treat musculoskeletal disorders in older patients. Here, in this present study, we have identified a set of phenotypic markers, namely, down-regulated expression of CD90 and upregulated expression of CD45, as age-defining markers for the bone marrow-derived MSCs. We also show that these phenotypic changes in aged MSCs correlate with their aging-mediated differentiation defects. We find that oxidative stress signaling leading to the activation of NF-κB plays an essential role in altering the phenotype and differentiation ability of the aged MSCs. We further show that treatment of aged MSCs with the conditioned medium (CM) derived from young MSCs (young-CM) restored their phenotype and differentiation potential to the young-like by ameliorating activation of NF-κB signaling in them. Similar changes could also be achieved by using an inhibitor of NF-κB signaling, showing that oxidative stress-induced NF-κB activation is the causative factor in the aging of MSCs. Additionally, we show that treating young MSCs with H2O2 mimics all the aging-mediated changes in them, underscoring the involvement of oxidative stress in the aging of MSCs. Overall, our data suggest that the altered expression of CD90 and CD45 surface markers can be used as a primary screen to identify the onset of aging in the MSCs, which can be quickly reversed by their in vitro treatment with young-CM or NF-κB inhibitor. Our study also puts the phenotypic characterization of MSCs in a clinical perspective.
    DOI:  https://doi.org/10.1089/scd.2022.0213
  8. Nat Commun. 2022 Nov 26. 13(1): 7301
    Greater genetic diversity is needed in human pluripotent stem cell models.
    Sulagna Ghosh, Ralda Nehme, Lindy E Barrett.
      
    DOI:  https://doi.org/10.1038/s41467-022-34940-z
  9. Cell Stem Cell. 2022 Dec 01. pii: S1934-5909(22)00451-9. [Epub ahead of print]29(12): 1685-1702.e22
    A reference human induced pluripotent stem cell line for large-scale collaborative studies.
    Caroline B Pantazis, Andrian Yang, Erika Lara, Justin A McDonough, Cornelis Blauwendraat, Lirong Peng, Hideyuki Oguro, Jitendra Kanaujiya, Jizhong Zou, David Sebesta, Gretchen Pratt, Erin Cross, Jeffrey Blockwick, Philip Buxton, Lauren Kinner-Bibeau, Constance Medura, Christopher Tompkins, Stephen Hughes, Marianita Santiana, Faraz Faghri, Mike A Nalls, Daniel Vitale, Shannon Ballard, Yue A Qi, Daniel M Ramos, Kailyn M Anderson, Julia Stadler, Priyanka Narayan, Jason Papademetriou, Luke Reilly, Matthew P Nelson, Sanya Aggarwal, Leah U Rosen, Peter Kirwan, Venkat Pisupati, Steven L Coon, Sonja W Scholz, Theresa Priebe, Miriam Öttl, Jian Dong, Marieke Meijer, Lara J M Janssen, Vanessa S Lourenco, Rik van der Kant, Dennis Crusius, Dominik Paquet, Ana-Caroline Raulin, Guojun Bu, Aaron Held, Brian J Wainger, Rebecca M C Gabriele, Jackie M Casey, Selina Wray, Dad Abu-Bonsrah, Clare L Parish, Melinda S Beccari, Don W Cleveland, Emmy Li, Indigo V L Rose, Martin Kampmann, Carles Calatayud Aristoy, Patrik Verstreken, Laurin Heinrich, Max Y Chen, Birgitt Schüle, Dan Dou, Erika L F Holzbaur, Maria Clara Zanellati, Richa Basundra, Mohanish Deshmukh, Sarah Cohen, Richa Khanna, Malavika Raman, Zachary S Nevin, Madeline Matia, Jonas Van Lent, Vincent Timmerman, Bruce R Conklin, Katherine Johnson Chase, Ke Zhang, Salome Funes, Daryl A Bosco, Lena Erlebach, Marc Welzer, Deborah Kronenberg-Versteeg, Guochang Lyu, Ernest Arenas, Elena Coccia, Lily Sarrafha, Tim Ahfeldt, John C Marioni, William C Skarnes, Mark R Cookson, Michael E Ward, Florian T Merkle.
      Human induced pluripotent stem cell (iPSC) lines are a powerful tool for studying development and disease, but the considerable phenotypic variation between lines makes it challenging to replicate key findings and integrate data across research groups. To address this issue, we sub-cloned candidate human iPSC lines and deeply characterized their genetic properties using whole genome sequencing, their genomic stability upon CRISPR-Cas9-based gene editing, and their phenotypic properties including differentiation to commonly used cell types. These studies identified KOLF2.1J as an all-around well-performing iPSC line. We then shared KOLF2.1J with groups around the world who tested its performance in head-to-head comparisons with their own preferred iPSC lines across a diverse range of differentiation protocols and functional assays. On the strength of these findings, we have made KOLF2.1J and its gene-edited derivative clones readily accessible to promote the standardization required for large-scale collaborative science in the stem cell field.
    Keywords:  CRISPR; differentiation; iPSC; karyotype; p53; pluripotent; reference; single-cell; stem cell; whole-genome
    DOI:  https://doi.org/10.1016/j.stem.2022.11.004
  10. Cell Stem Cell. 2022 Dec 01. pii: S1934-5909(22)00457-X. [Epub ahead of print]29(12): 1637-1652.e6
    Increased post-mitotic senescence in aged human neurons is a pathological feature of Alzheimer's disease.
    Joseph R Herdy, Larissa Traxler, Ravi K Agarwal, Lukas Karbacher, Johannes C M Schlachetzki, Lena Boehnke, Dina Zangwill, Doug Galasko, Christopher K Glass, Jerome Mertens, Fred H Gage.
      The concept of senescence as a phenomenon limited to proliferating cells has been challenged by growing evidence of senescence-like features in terminally differentiated cells, including neurons. The persistence of senescent cells late in life is associated with tissue dysfunction and increased risk of age-related disease. We found that Alzheimer's disease (AD) brains have significantly higher proportions of neurons that express senescence markers, and their distribution indicates bystander effects. AD patient-derived directly induced neurons (iNs) exhibit strong transcriptomic, epigenetic, and molecular biomarker signatures, indicating a specific human neuronal senescence-like state. AD iN single-cell transcriptomics revealed that senescent-like neurons face oncogenic challenges and metabolic dysfunction as well as display a pro-inflammatory signature. Integrative profiling of the inflammatory secretome of AD iNs and patient cerebral spinal fluid revealed a neuronal senescence-associated secretory phenotype that could trigger astrogliosis in human astrocytes. Finally, we show that targeting senescence-like neurons with senotherapeutics could be a strategy for preventing or treating AD.
    Keywords:  Alzheimer’s disease; SASP; aging; induced neurons (iNs); inflammation; senescence; senolytics
    DOI:  https://doi.org/10.1016/j.stem.2022.11.010
  11. Proc Natl Acad Sci U S A. 2022 Dec 06. 119(49): e2210766119
    Early diagnosis and treatment of Alzheimer's disease by targeting toxic soluble Aβ oligomers.
    Maram Habashi, Suresh Vutla, Kuldeep Tripathi, Sudipta Senapati, Pradeep S Chauhan, Anat Haviv-Chesner, Michal Richman, Samia-Ait Mohand, Véronique Dumulon-Perreault, Ramakotaiah Mulamreddy, Eitan Okun, Jordan H Chill, Brigitte Guérin, William D Lubell, Shai Rahimipour.
      Transient soluble oligomers of amyloid-β (Aβ) are toxic and accumulate early prior to insoluble plaque formation and cognitive impairment in Alzheimer's disease (AD). Synthetic cyclic D,L-α-peptides (e.g., 1) self-assemble into cross β-sheet nanotubes, react with early Aβ species (1-3 mers), and inhibit Aβ aggregation and toxicity in stoichiometric concentrations, in vitro. Employing a semicarbazide as an aza-glycine residue with an extra hydrogen-bond donor to tune nanotube assembly and amyloid engagement, [azaGly6]-1 inhibited Aβ aggregation and toxicity at substoichiometric concentrations. High-resolution NMR studies revealed dynamic interactions between [azaGly6]-1 and Aβ42 residues F19 and F20, which are pivotal for early dimerization and aggregation. In an AD mouse model, brain positron emission tomography (PET) imaging using stable 64Cu-labeled (aza)peptide tracers gave unprecedented early amyloid detection in 44-d presymptomatic animals. No tracer accumulation was detected in the cortex and hippocampus of 44-d-old 5xFAD mice; instead, intense PET signal was observed in the thalamus, from where Aβ oligomers may spread to other brain parts with disease progression. Compared with standard 11C-labeled Pittsburgh compound-B (11C-PIB), which binds specifically fibrillar Aβ plaques, 64Cu-labeled (aza)peptide gave superior contrast and uptake in young mouse brain correlating with Aβ oligomer levels. Effectively crossing the blood-brain barrier (BBB), peptide 1 and [azaGly6]-1 reduced Aβ oligomer levels, prolonged lifespan of AD transgenic Caenorhabditis elegans, and abated memory and behavioral deficits in nematode and murine AD models. Cyclic (aza)peptides offer novel promise for early AD diagnosis and therapy.
    Keywords:  Alzheimer’s disease; PET imaging; cyclic D,L-α-(aza)peptide; early diagnosis and therapy; soluble Aβ oligomers
    DOI:  https://doi.org/10.1073/pnas.2210766119
  12. J Cell Biol. 2023 Jan 02. pii: e202203070. [Epub ahead of print]222(1):
    Signal sequences encode information for protein folding in the endoplasmic reticulum.
    Sha Sun, Xia Li, Malaiyalam Mariappan.
      One-third of newly synthesized proteins in mammals are translocated into the endoplasmic reticulum (ER) through the Sec61 translocon. How protein translocation coordinates with chaperone availability in the ER to promote protein folding remains unclear. We find that marginally hydrophobic signal sequences and transmembrane domains cause transient retention at the Sec61 translocon and require the luminal BiP chaperone for efficient protein translocation. Using a substrate-trapping proteomic approach, we identify that nascent proteins bearing marginally hydrophobic signal sequences accumulate on the cytosolic side of the Sec61 translocon. Sec63 is co-translationally recruited to the translocation site and mediates BiP binding to incoming polypeptides. BiP binding not only releases translocationally paused nascent chains but also ensures protein folding in the ER. Increasing hydrophobicity of signal sequences bypasses Sec63/BiP-dependent translocation, but translocated proteins are prone to misfold and aggregate in the ER under limited BiP availability. Thus, the signal sequence-guided protein folding may explain why signal sequences are diverse and use multiple protein translocation pathways.
    DOI:  https://doi.org/10.1083/jcb.202203070
  13. J Alzheimers Dis. 2022 Nov 24.
    Beneficial Effect of a Small Pharmacologic Chaperone on the Established Alzheimer's Disease Phenotype.
    Jian-Guo Li, Benjamin E Blass, Domenico Praticò.
      BACKGROUND: The endosomal retromer complex system is a key controller for trafficking of proteins. Downregulation of its recognition core proteins, such as VPS35, is present in Alzheimer's disease (AD) brain, whereas its normalization prevents the development of AD pathology in a transgenic model with amyloid-β deposits and tau tangles.OBJECTIVE: Assess the effect of targeting VPS35 after the AD pathology and memory impairments have developed.
    METHODS: Twelve-month-old triple transgenic mice were treated with a small pharmacological chaperone, TPT-172, or vehicle for 14 weeks. At the end of this period, the effect of the drug on their phenotype was evaluated.
    RESULTS: While control mice had a decline of learning and memory, the group receiving the chaperone did not. Moreover, when compared with controls the treated mice had significantly less amyloid-β peptides and phosphorylated tau, elevation of post-synaptic protein, and reduction in astrocytes activation.
    CONCLUSION: Taken together, our findings demonstrate that pharmacologic stabilization of the retromer recognition core is beneficial also after the AD-like pathologic phenotype is established.
    Keywords:  Alzheimer’s disease; amyloid-β; pharmacological chaperone; retromer complex; tau protein
    DOI:  https://doi.org/10.3233/JAD-220869
  14. Immunol Res. 2022 Dec 01.
    Autophagic reprogramming of bone marrow-derived macrophages.
    Mayada Mazher, Yomna Adel Moqidem, Mona Zidan, Ahmed A Sayed, Ahmed Abdellatif.
      Macro-autophagy is a highly conserved catabolic process among eukaryotes affecting macrophages. This work studies the genetic regulatory network involving the interplay between autophagy and macrophage polarization (activation). Autophagy-related genes (Atgs) and differentially expressed genes (DEGs) of macrophage polarization (M1-M2) were predicted, and their regulatory networks constructed. Naïve (M0) mouse bone marrow-derived monocytes were differentiated into M1 and M2a. Validation of the targets of Smad1, LC3A and LC3B, Atg16L1, Atg7, IL-6, CD68, Arg-1, and Vamp7 was performed in vitro. Immunophenotyping by flow cytometry revealed three macrophage phenotypes: M0 (IL-6 + /CD68 +), M1 (IL-6 + /CD68 + /Arg-1 +), and M2a (CD68 + /Arg-1). Confocal microscopy revealed increased autophagy in both M1 and M2a and a significant increase in the pre-autophagosomes size and number. Bafilomycin A increased the expression of CD68 and Arg-1 in all cell lineages. In conclusion, our approach predicted the protein targets mediating the interplay between autophagy and macrophage polarization. We suggest that autophagy reprograms macrophage polarization via CD68, arginase 1, Atg16L1-1, and Atg16L1-3. The current findings provide a foundation for the future use of macrophages in immunotherapy of different autoimmune disorders.
    Keywords:  Autophagy; Autophagy-related genes; M1 macrophages; M2 macrophages; Macrophage polarization; Macrophages
    DOI:  https://doi.org/10.1007/s12026-022-09344-2
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