bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2023–03–26
eight papers selected by
Rich Giadone, Harvard University
  1. Hematopoietic stem cells preferentially traffic misfolded proteins to aggresomes and depend on aggrephagy to maintain protein homeostasis.
  2. The endoplasmic reticulum stress and unfolded protein response in Alzheimer's disease: a calcium dyshomeostasis perspective.
  3. RPL26/uL24 UFMylation is essential for ribosome-associated quality control at the endoplasmic reticulum.
  4. Cellular dynamics across aged human brains uncover a multicellular cascade leading to Alzheimer's disease.
  5. Pharmacologic Activation of an Integrated Stress Response Kinase Promotes Mitochondrial Remodeling.
  6. Morphological Analysis of Aging Hallmarks in the Central Nervous System of the Fast-Aging African Turquoise Killifish.
  7. Protein interaction studies in human induced neurons indicate convergent biology underlying autism spectrum disorders.
  8. A ubiquitin language communicates ribosomal distress.
  1. Cell Stem Cell. 2023 Mar 16. pii: S1934-5909(23)00071-1. [Epub ahead of print]
    Hematopoietic stem cells preferentially traffic misfolded proteins to aggresomes and depend on aggrephagy to maintain protein homeostasis.
    Bernadette A Chua, Connor J Lennan, Mary Jean Sunshine, Daniela Dreifke, Ashu Chawla, Eric J Bennett, Robert A J Signer.
      Hematopoietic stem cells (HSCs) regenerate blood cells throughout life. To preserve their fitness, HSCs are particularly dependent on maintaining protein homeostasis (proteostasis). However, how HSCs purge misfolded proteins is unknown. Here, we show that in contrast to most cells that primarily utilize the proteasome to degrade misfolded proteins, HSCs preferentially traffic misfolded proteins to aggresomes in a Bag3-dependent manner and depend on aggrephagy, a selective form of autophagy, to maintain proteostasis in vivo. When autophagy is disabled, HSCs compensate by increasing proteasome activity, but proteostasis is ultimately disrupted as protein aggregates accumulate and HSC function is impaired. Bag3-deficiency blunts aggresome formation in HSCs, resulting in protein aggregate accumulation, myeloid-biased differentiation, and diminished self-renewal activity. Furthermore, HSC aging is associated with a severe loss of aggresomes and reduced autophagic flux. Protein degradation pathways are thus specifically configured in young adult HSCs to preserve proteostasis and fitness but become dysregulated during aging.
    Keywords:  Bag3; aggrephagy; aggresome; aging; autophagy; hematopoietic stem cell; proteasome; protein degradation; proteostasis; stem cell
    DOI:  https://doi.org/10.1016/j.stem.2023.02.010
  2. Ageing Res Rev. 2023 Mar 20. pii: S1568-1637(23)00073-9. [Epub ahead of print] 101914
    The endoplasmic reticulum stress and unfolded protein response in Alzheimer's disease: a calcium dyshomeostasis perspective.
    Dmitry Lim, Laura Tapella, Giulia Dematteis, Armando A Genazzani, Marco Corazzari, Alexei Verkhratsky.
      Protein misfolding is prominent in early cellular pathology of Alzheimer's disease (AD), implicating pathophysiological significance of endoplasmic reticulum stress/unfolded protein response (ER stress/UPR) and highlighting it as a target for drug development. Experimental data from animal AD models and observations on human specimens are, however, inconsistent. ER stress and associated UPR are readily observed in in vitro AD cellular models and in some AD model animals. In the human brain, components and markers of ER stress as well as UPR transducers are observed at Braak stages III-VI associated with severe neuropathology and neuronal death. The picture, however, is further complicated by the brain region- and cell type-specificity of the AD-related pathology. Terms 'disturbed' or 'non-canonical' ER stress/UPR were used to describe the discrepancies between experimental data and the classic ER stress/UPR cascade. Here we discuss possible 'disturbing' or 'interfering' factors which may modify ER stress/UPR in the early AD pathogenesis. We focus on the dysregulation of the ER Ca2+ homeostasis, store-operated Ca2+ entry, and the interaction between the ER and mitochondria. We suggest that a detailed study of the CNS cell type-specific alterations of Ca2+ homeostasis in early AD may deepen our understanding of AD-related dysproteostasis.
    Keywords:  Alzheimer’s disease; Ca(2+) homeostasis; Ca(2+) signaling; ER stress/UPR; ER-mitochondria interaction; store-operated Ca(2+) entry
    DOI:  https://doi.org/10.1016/j.arr.2023.101914
  3. bioRxiv. 2023 Mar 09. pii: 2023.03.08.531792. [Epub ahead of print]
    RPL26/uL24 UFMylation is essential for ribosome-associated quality control at the endoplasmic reticulum.
    Francesco Scavone, Samantha C Gumbin, Paul A DaRosa, Ron R Kopito.
      Ribosomes that stall while translating cytosolic proteins are incapacitated by incomplete nascent chains, termed "arrest peptides" (APs) that are destroyed by the ubiquitin proteasome system (UPS) via a process known as the ribosome-associated quality control (RQC) pathway. By contrast, APs on ribosomes that stall while translocating secretory proteins into the endoplasmic reticulum (ER-APs) are shielded from cytosol by the ER membrane and the tightly sealed ribosome-translocon junction (RTJ). How this junction is breached to enable access of cytosolic UPS machinery and 26S proteasomes to translocon- and ribosome-obstructing ER-APs is not known. Here, we show that UPS and RQC-dependent degradation of ER-APs strictly requires conjugation of the ubiquitin-like (Ubl) protein UFM1 to 60S ribosomal subunits at the RTJ. Therefore, UFMylation of translocon-bound 60S subunits modulates the RTJ to promote access of proteasomes and RQC machinery to ER-APs.
    Significance Statement: UFM1 is a ubiquitin-like protein that is selectively conjugated to the large (60S) subunit of ribosomes bound to the endoplasmic reticulum (ER), but the specific biological function of this modification is unclear. Here, we show that UFMylation facilitates proteasome-mediated degradation of arrest polypeptides (APs) which are generated following splitting of ribosomes that stall during co-translational translocation of secretory proteins into the ER. We propose that UFMylation weakens the tightly sealed ribosome-translocon junction, thereby allowing the cytosolic ubiquitin-proteasome and ribosome-associated quality control machineries to access ER-APs.
    DOI:  https://doi.org/10.1101/2023.03.08.531792
  4. bioRxiv. 2023 Mar 09. pii: 2023.03.07.531493. [Epub ahead of print]
    Cellular dynamics across aged human brains uncover a multicellular cascade leading to Alzheimer's disease.
    Gilad Sahar Green, Masashi Fujita, Hyun-Sik Yang, Mariko Taga, Cristin McCabe, Anael Cain, Charles C White, Anna K Schmidtner, Lu Zeng, Yangling Wang, Aviv Regev, Vilas Menon, David A Bennett, Naomi Habib, Philip L De Jager.
      Alzheimer's Disease (AD) is a progressive neurodegenerative disease seen with advancing age. Recent studies have revealed diverse AD-associated cell states, yet when and how they impact the causal chain leading to AD remains unknown. To reconstruct the dynamics of the brain's cellular environment along the disease cascade and to distinguish between AD and aging effects, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.64 million single-nucleus RNA-seq profiles. We associated glial, vascular and neuronal subpopulations with AD-related traits for 424 aging individuals, and aligned them along the disease cascade using causal modeling. We identified two distinct lipid-associated microglial subpopulations, one contributed to amyloid-β proteinopathy while the other mediated the effect of amyloid-β in accelerating tau proteinopathy, as well as an astrocyte subpopulation that mediated the effect of tau on cognitive decline. To model the coordinated dynamics of the entire cellular environment we devised the BEYOND methodology which uncovered two distinct trajectories of brain aging that are defined by distinct sequences of changes in cellular communities. Older individuals are engaged in one of two possible trajectories, each associated with progressive changes in specific cellular communities that end with: (1) AD dementia or (2) alternative brain aging. Thus, we provide a cellular foundation for a new perspective of AD pathophysiology that could inform the development of new therapeutic interventions targeting cellular communities, while designing a different clinical management for those individuals on the path to AD or to alternative brain aging.
    DOI:  https://doi.org/10.1101/2023.03.07.531493
  5. bioRxiv. 2023 Mar 12. pii: 2023.03.11.532186. [Epub ahead of print]
    Pharmacologic Activation of an Integrated Stress Response Kinase Promotes Mitochondrial Remodeling.
    Valerie Perea, Kelsey R Baron, Vivian Dolina, Giovanni Aviles, Jessica D Rosarda, Xiaoyan Guo, Martin Kampmann, R Luke Wiseman.
      The integrated stress response (ISR) is a network of eIF2 α kinases, comprising PERK, GCN2, HRI, and PKR, that induce translational and transcriptional signaling in response to diverse insults. The PERK ISR kinase regulates mitochondria in response to endoplasmic reticulum (ER) stress. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activators of other ISR kinases to rescue ISR signaling and promote mitochondrial adaptation in cells lacking PERK. We show that the HRI activator BtdCPU and the GCN2 activator halofuginone activate ISR signaling and restore ER stress sensitivity in Perk- deficient cells. However, these compounds differentially impact mitochondria. BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and ISR activation through the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and altered mitochondrial respiration, mimicking the regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK activity and promote adaptive mitochondrial remodeling, highlighting the potential for pharmacologic ISR activation to mitigate mitochondrial dysfunction and motivating the pursuit of highly-selective ISR activators.
    DOI:  https://doi.org/10.1101/2023.03.11.532186
  6. Cold Spring Harb Protoc. 2023 Mar 20.
    Morphological Analysis of Aging Hallmarks in the Central Nervous System of the Fast-Aging African Turquoise Killifish.
    Steven Bergmans, Sophie Vanhunsel, Jolien Van Houcke, Valerie Mariën, Lut Arckens, Lieve Moons.
      As the number of elderly individuals is increasing in modern society, the need for a relevant gerontology model is higher than ever before. Aging can be defined by specific cellular hallmarks, described by López-Otín and colleagues, who provided a map which can be used to scavenge the aging tissue environment. As revealing the presence of individual hallmarks does not necessarily indicate aging, here we provide different (immuno)histochemical approaches that can be used to investigate several aging hallmarks-namely, genomic damage, mitochondrial dysfunction/oxidative stress, cellular senescence, stem cell exhaustion, and altered intercellular communication-in the killifish retina, optic tectum, and/or telencephalon at a morphological level. In combination with molecular and biochemical analysis of these aging hallmarks, this protocol offers the opportunity to fully characterize the aged killifish central nervous system.
    DOI:  https://doi.org/10.1101/pdb.prot107827
  7. Cell Genom. 2023 Mar 08. 3(3): 100250
    Protein interaction studies in human induced neurons indicate convergent biology underlying autism spectrum disorders.
    Greta Pintacuda, Yu-Han H Hsu, Kalliopi Tsafou, Ka Wan Li, Jacqueline M Martín, Jackson Riseman, Julia C Biagini, Joshua K T Ching, Daya Mena, Miguel A Gonzalez-Lozano, Shawn B Egri, Jake Jaffe, August B Smit, Nadine Fornelos, Kevin C Eggan, Kasper Lage.
      Autism spectrum disorders (ASDs) have been linked to genes with enriched expression in the brain, but it is unclear how these genes converge into cell-type-specific networks. We built a protein-protein interaction network for 13 ASD-associated genes in human excitatory neurons derived from induced pluripotent stem cells (iPSCs). The network contains newly reported interactions and is enriched for genetic and transcriptional perturbations observed in individuals with ASDs. We leveraged the network data to show that the ASD-linked brain-specific isoform of ANK2 is important for its interactions with synaptic proteins and to characterize a PTEN-AKAP8L interaction that influences neuronal growth. The IGF2BP1-3 complex emerged as a convergent point in the network that may regulate a transcriptional circuit of ASD-associated genes. Our findings showcase cell-type-specific interactomes as a framework to complement genetic and transcriptomic data and illustrate how both individual and convergent interactions can lead to biological insights into ASDs.
    Keywords:  IP-MS; autism spectrum disorders; exome sequencing; induced excitatory neurons; protein-protein interactions
    DOI:  https://doi.org/10.1016/j.xgen.2022.100250
  8. Semin Cell Dev Biol. 2023 Mar 22. pii: S1084-9521(23)00072-1. [Epub ahead of print]
    A ubiquitin language communicates ribosomal distress.
    Parissa C Monem, Joshua A Arribere.
      Cells entrust ribosomes with the critical task of identifying problematic mRNAs and facilitating their degradation. Ribosomes must communicate when they encounter and stall on an aberrant mRNA, lest they expose the cell to toxic and disease-causing proteins, or they jeopardize ribosome homeostasis and cellular translation. In recent years, ribosomal ubiquitination has emerged as a central signaling step in this process, and proteomic studies across labs and experimental systems show a myriad of ubiquitination sites throughout the ribosome. Work from many labs zeroed in on ubiquitination in one region of the small ribosomal subunit as being functionally significant, with the balance and exact ubiquitination sites determined by stall type, E3 ubiquitin ligases, and deubiquitinases. This review discusses the current literature surrounding ribosomal ubiquitination during translational stress and considers its role in committing translational complexes to decay.
    Keywords:  No-Go mRNA Decay (NGD); Nonstop mRNA Decay (NSD); Ribosome; Translation; Ubiquitin
    DOI:  https://doi.org/10.1016/j.semcdb.2023.03.009
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