bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2022–08–07
seven papers selected by
Rich Giadone, Harvard University
  1. Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities.
  2. Endoplasmic Reticulum Stress and Dysregulated Autophagy in Human Pancreatic Beta Cells.
  3. Brain aging, Alzheimer's disease, and the role of stem cells in primate comparative studies.
  4. Ca2+ signalling system initiated by endoplasmic reticulum stress stimulates PERK activation.
  5. Peripheral apoE4 enhances Alzheimer's pathology and impairs cognition by compromising cerebrovascular function.
  6. Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy.
  7. Glutamatergic Synapse Dysfunction in Drosophila Neuromuscular Junctions Can Be Rescued by Proteostasis Modulation.
  1. MedComm (2020). 2022 Sep;3(3): e161
    Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities.
    Chen Hu, Jing Yang, Ziping Qi, Hong Wu, Beilei Wang, Fengming Zou, Husheng Mei, Jing Liu, Wenchao Wang, Qingsong Liu.
      The heat shock proteins (HSPs) are ubiquitous and conserved protein families in both prokaryotic and eukaryotic organisms, and they maintain cellular proteostasis and protect cells from stresses. HSP protein families are classified based on their molecular weights, mainly including large HSPs, HSP90, HSP70, HSP60, HSP40, and small HSPs. They function as molecular chaperons in cells and work as an integrated network, participating in the folding of newly synthesized polypeptides, refolding metastable proteins, protein complex assembly, dissociating protein aggregate dissociation, and the degradation of misfolded proteins. In addition to their chaperone functions, they also play important roles in cell signaling transduction, cell cycle, and apoptosis regulation. Therefore, malfunction of HSPs is related with many diseases, including cancers, neurodegeneration, and other diseases. In this review, we describe the current understandings about the molecular mechanisms of the major HSP families including HSP90/HSP70/HSP60/HSP110 and small HSPs, how the HSPs keep the protein proteostasis and response to stresses, and we also discuss their roles in diseases and the recent exploration of HSP related therapy and diagnosis to modulate diseases. These research advances offer new prospects of HSPs as potential targets for therapeutic intervention.
    Keywords:  cancers; heat shock proteins; molecular chaperone; proteostasis; target therapy
    DOI:  https://doi.org/10.1002/mco2.161
  2. Diabetes Metab J. 2022 Jul;46(4): 533-542
    Endoplasmic Reticulum Stress and Dysregulated Autophagy in Human Pancreatic Beta Cells.
    Seoil Moon, Hye Seung Jung.
      Pancreatic beta cell homeostasis is crucial for the synthesis and secretion of insulin; disruption of homeostasis causes diabetes, and is a treatment target. Adaptation to endoplasmic reticulum (ER) stress through the unfolded protein response (UPR) and adequate regulation of autophagy, which are closely linked, play essential roles in this homeostasis. In diabetes, the UPR and autophagy are dysregulated, which leads to beta cell failure and death. Various studies have explored methods to preserve pancreatic beta cell function and mass by relieving ER stress and regulating autophagic activity. To promote clinical translation of these research results to potential therapeutics for diabetes, we summarize the current knowledge on ER stress and autophagy in human insulin-secreting cells.
    Keywords:  Autophagy; Diabetes mellitus; Endoplasmic reticulum stress; Humans; Insulin secretion; Insulin-secreting cells; Unfolded protein response
    DOI:  https://doi.org/10.4093/dmj.2022.0070
  3. J Comp Neurol. 2022 Aug 05.
    Brain aging, Alzheimer's disease, and the role of stem cells in primate comparative studies.
    Isabel August, Katerina Semendeferi, Maria Carolina Marchetto.
      Alzheimer's disease (AD) is a progressive neurodegenerative disease that is ultimately fatal. Currently, millions of Americans are living with AD, and this number is predicted to grow with increases in the aging population. Interestingly, despite the prevalence of AD in human populations, the full AD phenotype has not been observed in any nonhuman primate (NHP) species, and it has been suggested that NHPs are immune to neurodegenerative diseases such as AD. Here, we review the typical age-related changes and pathologies in humans along with the neuropathologic changes associated with AD, and we place this information in the context of the comparative neuropathology of NHPs. We further propose the use of induced pluripotent stem cell technology as a way of addressing initial molecular processes and changes that occur in neurons and glia (in both humans and NHPs) when exposed to AD-inducing pathology prior to cell death.
    Keywords:  alzheimer's disease; brain aging; primate; stem cells
    DOI:  https://doi.org/10.1002/cne.25394
  4. Cell Calcium. 2022 Jul 20. pii: S0143-4160(22)00095-1. [Epub ahead of print]106 102622
    Ca2+ signalling system initiated by endoplasmic reticulum stress stimulates PERK activation.
    Constanza Feliziani, Macarena Fernandez, Gonzalo Quassollo, Deborah Holstein, Sebastián M Bairo, James C Paton, Adrienne W Paton, Juan de Batista, James D Lechleiter, Mariana Bollo.
      The accumulation of unfolded proteins within the Endoplasmic Reticulum (ER) activates a signal transduction pathway termed the unfolded protein response (UPR), which attempts to restore ER homoeostasis. If this cannot be done, UPR signalling ultimately induces apoptosis. Ca2+ depletion in the ER is a potent inducer of ER stress. Despite the ubiquity of Ca2+ as an intracellular messenger, the precise mechanism(s) by which Ca2+ release affects the UPR remains unknown. Tethering a genetically encoded Ca2+ indicator (GCamP6) to the ER membrane revealed novel Ca2+ signalling events initiated by Ca2+ microdomains in human astrocytes under ER stress, induced by tunicamycin (Tm), an N-glycosylation inhibitor, as well as in a cell model deficient in all three inositol triphosphate receptor isoforms. Pharmacological and molecular studies indicate that these local events are mediated by translocons and that the Ca2+ microdomains impact (PKR)-like-ER kinase (PERK), an UPR sensor, activation. These findings reveal the existence of a Ca2+ signal mechanism by which stressor-mediated Ca2+ release regulates ER stress.
    Keywords:  (PKR)-like-ER kinase (PERK); Calcium signalling; Inositol triphosphate receptor; Translocon; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.ceca.2022.102622
  5. Nat Neurosci. 2022 Aug;25(8): 1020-1033
    Peripheral apoE4 enhances Alzheimer's pathology and impairs cognition by compromising cerebrovascular function.
    Chia-Chen Liu, Jing Zhao, Yuan Fu, Yasuteru Inoue, Yingxue Ren, Yuanxin Chen, Sydney V Doss, Francis Shue, Suren Jeevaratnam, Ligia Bastea, Na Wang, Yuka A Martens, Wenhui Qiao, Minghui Wang, Na Zhao, Lin Jia, Yu Yamazaki, Akari Yamazaki, Cassandra L Rosenberg, Zhen Wang, Dehui Kong, Zonghua Li, Lindsey A Kuchenbecker, Zachary A Trottier, Lindsey Felton, Justin Rogers, Zachary S Quicksall, Cynthia Linares, Joshua Knight, Yixing Chen, Aishe Kurti, Takahisa Kanekiyo, John D Fryer, Yan W Asmann, Peter Storz, Xusheng Wang, Junmin Peng, Bin Zhang, Betty Y S Kim, Guojun Bu.
      The ε4 allele of the apolipoprotein E (APOE) gene, a genetic risk factor for Alzheimer's disease, is abundantly expressed in both the brain and periphery. Here, we present evidence that peripheral apoE isoforms, separated from those in the brain by the blood-brain barrier, differentially impact Alzheimer's disease pathogenesis and cognition. To evaluate the function of peripheral apoE, we developed conditional mouse models expressing human APOE3 or APOE4 in the liver with no detectable apoE in the brain. Liver-expressed apoE4 compromised synaptic plasticity and cognition by impairing cerebrovascular functions. Plasma proteome profiling revealed apoE isoform-dependent functional pathways highlighting cell adhesion, lipoprotein metabolism and complement activation. ApoE3 plasma from young mice improved cognition and reduced vessel-associated gliosis when transfused into aged mice, whereas apoE4 compromised the beneficial effects of young plasma. A human induced pluripotent stem cell-derived endothelial cell model recapitulated the plasma apoE isoform-specific effect on endothelial integrity, further supporting a vascular-related mechanism. Upon breeding with amyloid model mice, liver-expressed apoE4 exacerbated brain amyloid pathology, whereas apoE3 reduced it. Our findings demonstrate pathogenic effects of peripheral apoE4, providing a strong rationale for targeting peripheral apoE to treat Alzheimer's disease.
    DOI:  https://doi.org/10.1038/s41593-022-01127-0
  6. Nat Commun. 2022 Aug 01. 13(1): 4444
    Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy.
    Annie Lee, Chandana Kondapalli, Daniel M Virga, Tommy L Lewis, So Yeon Koo, Archana Ashok, Georges Mairet-Coello, Sebastien Herzig, Marc Foretz, Benoit Viollet, Reuben Shaw, Andrew Sproul, Franck Polleux.
      During the early stages of Alzheimer's disease (AD) in both mouse models and human patients, soluble forms of Amyloid-β 1-42 oligomers (Aβ42o) trigger loss of excitatory synapses (synaptotoxicity) in cortical and hippocampal pyramidal neurons (PNs) prior to the formation of insoluble amyloid plaques. In a transgenic AD mouse model, we observed a spatially restricted structural remodeling of mitochondria in the apical tufts of CA1 PNs dendrites corresponding to the dendritic domain where the earliest synaptic loss is detected in vivo. We also observed AMPK over-activation as well as increased fragmentation and loss of mitochondrial biomass in Ngn2-induced neurons derived from a new APPSwe/Swe knockin human ES cell line. We demonstrate that Aβ42o-dependent over-activation of the CAMKK2-AMPK kinase dyad mediates synaptic loss through coordinated phosphorylation of MFF-dependent mitochondrial fission and ULK2-dependent mitophagy. Our results uncover a unifying stress-response pathway causally linking Aβ42o-dependent structural remodeling of dendritic mitochondria to synaptic loss.
    DOI:  https://doi.org/10.1038/s41467-022-32130-5
  7. Front Mol Neurosci. 2022 ;15 842772
    Glutamatergic Synapse Dysfunction in Drosophila Neuromuscular Junctions Can Be Rescued by Proteostasis Modulation.
    Anushka Chakravorty, Ankit Sharma, Vasu Sheeba, Ravi Manjithaya.
      Glutamate is the major excitatory neurotransmitter in the nervous system, and the Drosophila glutamatergic neuromuscular junctions (NMJs) offer a tractable platform to understand excitatory synapse biology both in health and disease. Synaptopathies are neurodegenerative diseases that are associated with synaptic dysfunction and often display compromised proteostasis. One such rare, progressive neurodegenerative condition, Spinocerebellar Ataxia Type 3 (SCA3) or Machado-Joseph Disease (MJD), is characterized by cerebellar ataxia, Parkinsonism, and degeneration of motor neuron synapses. While the polyQ repeat mutant protein ataxin-3 is implicated in MJD, it is unclear how it leads to impaired synaptic function. In this study, we indicated that a Drosophila model of MJD recapitulates characteristics of neurodegenerative disorders marked by motor neuron dysfunction. Expression of 78 polyQ repeats of mutant ataxin-3 protein in Drosophila motor neurons resulted in behavioral defects, such as impaired locomotion in both larval and adult stages. Furthermore, defects in eclosion and lifespan were observed in adult flies. Detailed characterization of larval glutamatergic neuromuscular junctions (NMJs) revealed defects in morphological features along with compromised NMJ functioning. Autophagy, one of the key proteostasis pathways, is known to be impaired in the case of several synaptopathies. Our study reveals that overexpression of the autophagy-related protein Atg8a rescued behavioral defects. Thus, we present a model for glutamatergic synapse dysfunction that recapitulates synaptic and behavioral deficits and show that it is an amenable system for carrying out genetic and chemical biology screens to identify potential therapeutic targets for synaptopathies.
    Keywords:  Drosophila neuromuscular junctions; Spinocerebellar Ataxia Type 3; autophagy; glutamatergic synapse; synapse dysfunction; synaptopathy
    DOI:  https://doi.org/10.3389/fnmol.2022.842772
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