bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2023–03–19
seven papers selected by
Rich Giadone, Harvard University
  1. Dysregulated proteostasis network in neuronal diseases.
  2. Non-canonical autophagy in aging and age-related diseases.
  3. Compromised autophagy and mitophagy in brain ageing and Alzheimer's diseases.
  4. Inter-tissue communication of mitochondrial stress in aging.
  5. Heat shock factor 1 promotes neurite outgrowth and suppresses inflammation in the severed spinal cord of geckos.
  6. A multi-omics view of neuronal subcellular protein synthesis.
  7. The role of O-GlcNAcylation in development.
  1. Front Cell Dev Biol. 2023 ;11 1075215
    Dysregulated proteostasis network in neuronal diseases.
    Ching-San Tseng, Yu-Wen Chao, Yi-Hsiang Liu, Yi-Shuian Huang, Hsu-Wen Chao.
      Long-term maintenance of synaptic connections is important for brain function, which depends on varying proteostatic regulations to govern the functional integrity of neuronal proteomes. Proteostasis supports an interconnection of pathways that regulates the fate of proteins from synthesis to degradation. Defects in proteostatic signaling are associated with age-related functional decline and neurodegenerative diseases. Recent studies have advanced our knowledge of how cells have evolved distinct mechanisms to safely control protein homeostasis during synthesis, folding and degradation, and in different subcellular organelles and compartments. Neurodegeneration occurs when these protein quality controls are compromised by accumulated pathogenic proteins or aging to an irreversible state. Consequently, several therapeutic strategies, such as targeting the unfolded protein response and autophagy pathways, have been developed to reduce the burden of misfolded proteins and proved useful in animal models. Here, we present a brief overview of the molecular mechanisms involved in maintaining proteostatic networks, along with some examples linking dysregulated proteostasis to neuronal diseases.
    Keywords:  mRNA translation; neurodegeneration; post-translation modification; protein degradation; stress granule
    DOI:  https://doi.org/10.3389/fcell.2023.1075215
  2. Front Cell Dev Biol. 2023 ;11 1137870
    Non-canonical autophagy in aging and age-related diseases.
    Anita V Kumar, Joslyn Mills.
      Autophagy, one of the arms of proteostasis, influences aging and age-related diseases. Recently, the discovery of additional roles of autophagy-related proteins in non-canonical degradation and secretion has revealed alternative fates of autophagic cargo. Some of these non-canonical pathways have been linked to neurodegenerative diseases and improving the understanding of this link is crucial for their potential targetability in aging and age-related diseases. This review discusses recent investigations of the involvement of non-canonical autophagy players and pathways in age-related diseases that are now beginning to be discovered. Unraveling these pathways and their relation to classical autophagy could unearth a fascinating new layer of proteostasis regulation during normal aging and in longevity.
    Keywords:  LANDO; LAP (LC3 associated phagocytosis); aging; neurodegenerative diseasaes; non-canonical autophagy; secretory autophagy
    DOI:  https://doi.org/10.3389/fcell.2023.1137870
  3. Aging Brain. 2022 ;2 100056
    Compromised autophagy and mitophagy in brain ageing and Alzheimer's diseases.
    Domenica Caponio, Kateřina Veverová, Shi-Qi Zhang, Liu Shi, Garry Wong, Martin Vyhnalek, Evandro F Fang.
      Alzheimer's disease (AD) is one of the most persistent and devastating neurodegenerative disorders of old age, and is characterized clinically by an insidious onset and a gradual, progressive deterioration of cognitive abilities, ranging from loss of memory to impairment of judgement and reasoning. Despite years of research, an effective cure is still not available. Autophagy is the cellular 'garbage' clearance system which plays fundamental roles in neurogenesis, neuronal development and activity, and brain health, including memory and learning. A selective sub-type of autophagy is mitophagy which recognizes and degrades damaged or superfluous mitochondria to maintain a healthy and necessary cellular mitochondrial pool. However, emerging evidence from animal models and human samples suggests an age-dependent reduction of autophagy and mitophagy, which are also compromised in AD. Upregulation of autophagy/mitophagy slows down memory loss and ameliorates clinical features in animal models of AD. In this review, we give an overview of autophagy and mitophagy and their link to the progression of AD. We also summarize approaches to upregulate autophagy/mitophagy. We hypothesize that age-dependent compromised autophagy/mitophagy is a cause of brain ageing and a risk factor for AD, while restoration of autophagy/mitophagy to more youthful levels could return the brain to health.
    Keywords:  Ageing; Alzheimer’s disease; Autophagy; Mitophagy
    DOI:  https://doi.org/10.1016/j.nbas.2022.100056
  4. Yi Chuan. 2023 Mar 20. 45(3): 187-197
    Inter-tissue communication of mitochondrial stress in aging.
    Qian Zhang, Zihao Wang, Ye Tian.
      The protein homeostasis in mitochondria is critical for the normal physiological function of cells. To cope with mitochondrial stress, cells elicit specific stress response named mitochondrial unfolded protein response (UPRmt), to maintain mitochondrial homeostasis and repair mitochondrial function. Although severe damage to mitochondria is detrimental, studies in worms, flies, and mice have shown that mild mitochondrial damage promotes longevity by activating UPRmt. Interestingly, UPRmt can also be induced in a cell non-autonomous manner in cells or tissues which are not directly experiencing mitochondrial stress. The secreted molecules called "mitokine" are responsible for the mitochondrial stress communication between different tissues. This inter-tissue regulation of mitochondrial stress response systematically coordinates the adaptation ability which is closely associated with aging and a variety of diseases such as neurodegeneration and cancer. In this review, we summarize recent advances about inter-tissue mitochondrial stress communications, and introduce the current knowledge about the "mitokine" and its regulation on aging for further studies.
    Keywords:  aging; inter-tissue regulation; mitochondrial unfolded protein response; protein homeostasis
    DOI:  https://doi.org/10.16288/j.yczz.22-416
  5. Neural Regen Res. 2023 Sep;18(9): 2011-2018
    Heat shock factor 1 promotes neurite outgrowth and suppresses inflammation in the severed spinal cord of geckos.
    Bing-Qiang He, Ai-Cheng Li, Yu-Xuan Hou, Hui Li, Xing-Yuan Zhang, Hui-Fei Hao, Hong-Hua Song, Ri-Xin Cai, Ying-Jie Wang, Yue Zhou, Yong-Jun Wang.
      The low intrinsic growth capacity of neurons and an injury-induced inhibitory milieu are major contributors to the failure of sensory and motor functional recovery following spinal cord injury. Heat shock transcription factor 1 (HSF1), a master regulator of the heat shock response, plays neurogenetic and neuroprotective roles in the damaged or diseased central nervous system. However, the underlying mechanism has not been fully elucidated. In the present study, we used a gecko model of spontaneous nerve regeneration to investigate the potential roles of gecko HSF1 (gHSF1) in the regulation of neurite outgrowth and inflammatory inhibition of macrophages following spinal cord injury. gHSF1 expression in neurons and microglia at the lesion site increased dramatically immediately after tail amputation. gHSF1 overexpression in gecko primary neurons significantly promoted axonal growth by suppressing the expression of suppressor of cytokine signaling-3, and facilitated neuronal survival via activation of the mitogen-activated extracellular signal-regulated kinase/extracellular regulated protein kinases and phosphatidylinositol 3-kinase/protein kinase B pathways. Furthermore, gHSF1 efficiently inhibited the macrophage-mediated inflammatory response by inactivating IkappaB-alpha/NF-kappaB signaling. Our findings show that HSF1 plays dual roles in promoting axonal regrowth and inhibiting leukocyte inflammation, and provide new avenues of investigation for promoting spinal cord injury repair in mammals.
    Keywords:  apoptosis; gecko; heat shock factor 1; inflammation; neuron; regeneration; spinal cord; suppressor of cytokine signaling-3
    DOI:  https://doi.org/10.4103/1673-5374.366495
  6. Curr Opin Neurobiol. 2023 Mar 11. pii: S0959-4388(23)00030-2. [Epub ahead of print]80 102705
    A multi-omics view of neuronal subcellular protein synthesis.
    Chao Sun, Erin Schuman.
      While it has long been known that protein synthesis is necessary for long-term memory in the brain, the logistics of neuronal protein synthesis is complicated by the extensive subcellular compartmentalization of the neuron. Local protein synthesis solves many of the logistic problems posed by the extreme complexity of dendritic and axonal arbors and the huge number of synapses. Here we review recent multi-omic and quantitative studies that elaborate a systems view of decentralized neuronal protein synthesis. We highlight recent insights from the transcriptomic, translatomic, and proteomic levels, discuss the nuanced logic of local protein synthesis for different protein features, and list the missing information needed to build a comprehensive logistic model for neuronal protein supply.
    DOI:  https://doi.org/10.1016/j.conb.2023.102705
  7. Development. 2023 Mar 15. pii: dev201370. [Epub ahead of print]150(6):
    The role of O-GlcNAcylation in development.
    Ignacy Czajewski, Daan M F van Aalten.
      O-GlcNAcylation is a dynamic post-translational modification performed by two opposing enzymes: O-GlcNAc transferase and O-GlcNAcase. O-GlcNAcylation is generally believed to act as a metabolic integrator in numerous signalling pathways. The stoichiometry of this modification is tightly controlled throughout all stages of development, with both hypo/hyper O-GlcNAcylation resulting in broad defects. In this Primer, we discuss the role of O-GlcNAcylation in developmental processes from stem cell maintenance and differentiation to cell and tissue morphogenesis.
    Keywords:  Differentiation; Glycosylation; O-GlcNAcylation; Polycomb group proteins; Stem cells
    DOI:  https://doi.org/10.1242/dev.201370
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