bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2023–01–01
six papers selected by
Rich Giadone, Harvard University
  1. The roles of HSP40/DNAJ protein family in neurodegenerative diseases.
  2. Chemical Chaperones to Inhibit Endoplasmic Reticulum Stress: Implications in Diseases.
  3. Transplanting rejuvenated blood stem cells extends lifespan of aged immunocompromised mice.
  4. Molecular and spatial signatures of mouse brain aging at single-cell resolution.
  5. Cytosolic stress granules relieve the ubiquitin-proteasome system in the nuclear compartment.
  6. Alzheimer's-Associated Upregulation of Mitochondria-Associated ER Membranes After Traumatic Brain Injury.
  1. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2022 Nov 25. 51(5): 640-646
    The roles of HSP40/DNAJ protein family in neurodegenerative diseases.
    Yinghui He, Zhiping Wang.
      Molecular chaperones and co-chaperones facilitate the assembly of newly synthesized polypeptides and refolding of unfolded or misfolded proteins, thereby maintaining protein homeostasis in cells. As co-chaperones of the master chaperone heat shock protein (HSP) 70, the HSP40 (DNAJ) proteins are largest chaperone family in eukaryotic cells. They contain a characteristic J-domain which mediates interaction with HSP70, thereby helping protein folding. It is well perceived that protein homeostasis is vital for neuronal health. DNAJ family proteins have been linked to the occurrence and progression of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar ataxia, Charcot-Marie-Tooth disease, spinal muscular atrophy, distal hereditary motor neuropathy, limb-girdle type muscular dystrophy, neuronal ceroid lipofuscinosis and essential tremor in recent studies. DNAJA1 effectively degrades huntington aggregates; DNAJB1 can degrade protein aggregates ataxin-3; DNAJB2 can inhibit the formation of huntington aggregates; DNAJB6 can inhibit the aggregation of Aβ 42 and α-synuclein; DNAJC5 can promote the release of TDP-43, τ protein, and α-synuclein into the extracellular space. Mutations in the essential tremor-associated DNAJC13 gene can prevent endosome protein trafficking. This article reviews the mechanism of DNAJ protein family in neurodegenerative diseases.
    Keywords:  DNAJ; HSP40; Molecular chaperones; Neurodegenerative diseases; Protein homeostasis; Review
    DOI:  https://doi.org/10.3724/zdxbyxb-2021-0406
  2. Drug Des Devel Ther. 2022 ;16 4385-4397
    Chemical Chaperones to Inhibit Endoplasmic Reticulum Stress: Implications in Diseases.
    Jae-Ho Jeon, Somyoung Im, Hyo Shin Kim, Dongyun Lee, Kwiwan Jeong, Jin-Mo Ku, Tae-Gyu Nam.
      The endoplasmic reticulum (ER) is responsible for structural transformation or folding of de novo proteins for transport to the Golgi. When the folding capacity of the ER is exceeded or excessive accumulation of misfolded proteins occurs, the ER enters a stressed condition (ER stress) and unfolded protein responses (UPR) are triggered in order to rescue cells from the stress. Recovery of ER proceeds toward either survival or cell apoptosis. ER stress is implicated in many pathologies, such as diabetes, cardiovascular diseases, inflammatory diseases, neurodegeneration, and lysosomal storage diseases. As a survival or adaptation mechanism, chaperone molecules are upregulated to manage ER stress. Chemical versions of chaperone have been developed in search of drug candidates for ER stress-related diseases. In this review, synthetic or semi-synthetic chemical chaperones are categorized according to potential therapeutic area and listed along with their chemical structure and activity. Although only a few chemical chaperones have been approved as pharmaceutical drugs, a dramatic increase in literatures over the recent decades indicates enormous amount of efforts paid by many researchers. The efforts warrant clearer understanding of ER stress and the related diseases and consequently will offer a promising drug discovery platform with chaperone activity.
    Keywords:  cardiovascular disease; chemical chaperone; diabetes; drug discovery; endoplasmic reticulum stress; lysosomal storage disease; neurodegeneration; unfolded protein response
    DOI:  https://doi.org/10.2147/DDDT.S393816
  3. NPJ Regen Med. 2022 Dec 29. 7(1): 78
    Transplanting rejuvenated blood stem cells extends lifespan of aged immunocompromised mice.
    Sara Montserrat-Vazquez, Noelle J Ali, Francesca Matteini, Javier Lozano, Tu Zhaowei, Eva Mejia-Ramirez, Gina Marka, Angelika Vollmer, Karin Soller, Mehmet Sacma, Vadim Sakk, Loris Mularoni, Jan Philipp Mallm, Mireya Plass, Yi Zheng, Hartmut Geiger, M Carolina Florian.
      One goal of regenerative medicine is to rejuvenate tissues and extend lifespan by restoring the function of endogenous aged stem cells. However, evidence that somatic stem cells can be targeted in vivo to extend lifespan is still lacking. Here, we demonstrate that after a short systemic treatment with a specific inhibitor of the small RhoGTPase Cdc42 (CASIN), transplanting aged hematopoietic stem cells (HSCs) from treated mice is sufficient to extend the healthspan and lifespan of aged immunocompromised mice without additional treatment. In detail, we show that systemic CASIN treatment improves strength and endurance of aged mice by increasing the myogenic regenerative potential of aged skeletal muscle stem cells. Further, we show that CASIN modifies niche localization and H4K16ac polarity of HSCs in vivo. Single-cell profiling reveals changes in HSC transcriptome, which underlie enhanced lymphoid and regenerative capacity in serial transplantation assays. Overall, we provide proof-of-concept evidence that a short systemic treatment to decrease Cdc42 activity improves the regenerative capacity of different endogenous aged stem cells in vivo, and that rejuvenated HSCs exert a broad systemic effect sufficient to extend murine health- and lifespan.
    DOI:  https://doi.org/10.1038/s41536-022-00275-y
  4. Cell. 2022 Dec 21. pii: S0092-8674(22)01523-9. [Epub ahead of print]
    Molecular and spatial signatures of mouse brain aging at single-cell resolution.
    William E Allen, Timothy R Blosser, Zuri A Sullivan, Catherine Dulac, Xiaowei Zhuang.
      The diversity and complex organization of cells in the brain have hindered systematic characterization of age-related changes in its cellular and molecular architecture, limiting our ability to understand the mechanisms underlying its functional decline during aging. Here, we generated a high-resolution cell atlas of brain aging within the frontal cortex and striatum using spatially resolved single-cell transcriptomics and quantified changes in gene expression and spatial organization of major cell types in these regions over the mouse lifespan. We observed substantially more pronounced changes in cell state, gene expression, and spatial organization of non-neuronal cells over neurons. Our data revealed molecular and spatial signatures of glial and immune cell activation during aging, particularly enriched in the subcortical white matter, and identified both similarities and notable differences in cell-activation patterns induced by aging and systemic inflammatory challenge. These results provide critical insights into age-related decline and inflammation in the brain.
    Keywords:  LPS; MERFISH; astrocyte; brain aging; inflammation; microglia; oligodendrocyte; single-cell RNA sequencing; single-cell transcriptomics; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.cell.2022.12.010
  5. EMBO J. 2022 Dec 27. e111802
    Cytosolic stress granules relieve the ubiquitin-proteasome system in the nuclear compartment.
    Shanshan Xu, Maria E Gierisch, Anna Katharina Schellhaus, Ina Poser, Simon Alberti, Florian A Salomons, Nico P Dantuma.
      The role of cytosolic stress granules in the integrated stress response has remained largely enigmatic. Here, we studied the functionality of the ubiquitin-proteasome system (UPS) in cells that were unable to form stress granules. Surprisingly, the inability of cells to form cytosolic stress granules had primarily a negative impact on the functionality of the nuclear UPS. While defective ribosome products (DRiPs) accumulated at stress granules in thermally stressed control cells, they localized to nucleoli in stress granule-deficient cells. The nuclear localization of DRiPs was accompanied by redistribution and enhanced degradation of SUMOylated proteins. Depletion of the SUMO-targeted ubiquitin ligase RNF4, which targets SUMOylated misfolded proteins for proteasomal degradation, largely restored the functionality of the UPS in the nuclear compartment in stress granule-deficient cells. Stress granule-deficient cells showed an increase in the formation of mutant ataxin-1 nuclear inclusions when exposed to thermal stress. Our data reveal that stress granules play an important role in the sequestration of cytosolic misfolded proteins, thereby preventing these proteins from accumulating in the nucleus, where they would otherwise infringe nuclear proteostasis.
    Keywords:  SUMO; protein quality control; proteostasis; stress granules; ubiquitin-proteasome system
    DOI:  https://doi.org/10.15252/embj.2022111802
  6. Cell Mol Neurobiol. 2022 Dec 26.
    Alzheimer's-Associated Upregulation of Mitochondria-Associated ER Membranes After Traumatic Brain Injury.
    Rishi R Agrawal, Delfina Larrea, Yimeng Xu, Lingyan Shi, Hylde Zirpoli, Leslie G Cummins, Valentina Emmanuele, Donghui Song, Taekyung D Yun, Frank P Macaluso, Wei Min, Steven G Kernie, Richard J Deckelbaum, Estela Area-Gomez.
      Traumatic brain injury (TBI) can lead to neurodegenerative diseases such as Alzheimer's disease (AD) through mechanisms that remain incompletely characterized. Similar to AD, TBI models present with cellular metabolic alterations and modulated cleavage of amyloid precursor protein (APP). Specifically, AD and TBI tissues display increases in amyloid-β as well as its precursor, the APP C-terminal fragment of 99 a.a. (C99). Our recent data in cell models of AD indicate that C99, due to its affinity for cholesterol, induces the formation of transient lipid raft domains in the ER known as mitochondria-associated endoplasmic reticulum (ER) membranes ("MAM" domains). The formation of these domains recruits and activates specific lipid metabolic enzymes that regulate cellular cholesterol trafficking and sphingolipid turnover. Increased C99 levels in AD cell models promote MAM formation and significantly modulate cellular lipid homeostasis. Here, these phenotypes were recapitulated in the controlled cortical impact (CCI) model of TBI in adult mice. Specifically, the injured cortex and hippocampus displayed significant increases in C99 and MAM activity, as measured by phospholipid synthesis, sphingomyelinase activity and cholesterol turnover. In addition, our cell type-specific lipidomics analyses revealed significant changes in microglial lipid composition that are consistent with the observed alterations in MAM-resident enzymes. Altogether, we propose that alterations in the regulation of MAM and relevant lipid metabolic pathways could contribute to the epidemiological connection between TBI and AD.
    Keywords:  Alzheimer’s; Brain injury; Contact sites; Lipids; Mitochondria; Neurodegeneration
    DOI:  https://doi.org/10.1007/s10571-022-01299-0
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