The Biology of Proteostasis in Aging and Disease
TLDR
The composition, function, and organizational properties of the PN are reviewed in the context of individual cells and entire organisms and the mechanisms by which disruption of thePN, and related stress response pathways, contributes to the initiation and progression of disease are discussed.Abstract:
Loss of protein homeostasis (proteostasis) is a common feature of aging and disease that is characterized by the appearance of nonnative protein aggregates in various tissues. Protein aggregation is routinely suppressed by the proteostasis network (PN), a collection of macromolecular machines that operate in diverse ways to maintain proteome integrity across subcellular compartments and between tissues to ensure a healthy life span. Here, we review the composition, function, and organizational properties of the PN in the context of individual cells and entire organisms and discuss the mechanisms by which disruption of the PN, and related stress response pathways, contributes to the initiation and progression of disease. We explore emerging evidence that disease susceptibility arises from early changes in the composition and activity of the PN and propose that a more complete understanding of the temporal and spatial properties of the PN will enhance our ability to develop effective treatments for protein conformational diseases.read more
Citations
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Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade
TL;DR: This review describes this field of science with particular reference to the advances that have been made over the last decade in understanding of its fundamental nature and consequences and shows evidence that a complex proteostasis network actively combats protein aggregation.
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The integrated stress response.
Karolina Pakos-Zebrucka,Izabela Koryga,Katarzyna Mnich,Mila Ljujic,Afshin Samali,Adrienne M. Gorman +5 more
TL;DR: Current understanding of the ISR signaling is reviewed and how it regulates cell fate under diverse types of stress is reviewed.
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Single-cell transcriptomic analysis of Alzheimer’s disease
Hansruedi Mathys,Hansruedi Mathys,Jose Davila-Velderrain,Jose Davila-Velderrain,Zhuyu Peng,Zhuyu Peng,Fan Gao,Fan Gao,Shahin Mohammadi,Shahin Mohammadi,Jennie Z. Young,Jennie Z. Young,Madhvi Menon,Madhvi Menon,Liang He,Liang He,Fatema Abdurrob,Fatema Abdurrob,Xueqiao Jiang,Xueqiao Jiang,Anthony J Martorell,Anthony J Martorell,Richard M. Ransohoff,Brian P. Hafler,David A. Bennett,Manolis Kellis,Manolis Kellis,Li-Huei Tsai,Li-Huei Tsai,Li-Huei Tsai +29 more
TL;DR: Single-cell transcriptomics from 48 individuals with varying degrees of Alzheimer's disease pathology demonstrates that gene-expression changes in Alzheimer’s disease are both cell-type specific and shared, and that transcriptional responses show sexual dimorphism.
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The Cellular Phase of Alzheimer’s Disease
TL;DR: Evidence supporting a long, complex cellular phase consisting of feedback and feedforward responses of astrocytes, microglia, and vasculature is reviewed.
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In vivo aspects of protein folding and quality control
TL;DR: A new view of protein folding is emerging, whereby the energy landscapes that proteins navigate during folding in vivo may differ substantially from those observed during refolding in vitro.
References
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Journal ArticleDOI
Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis
TL;DR: Tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O–2 to O2 and H2O2 is reported.
Journal ArticleDOI
Protein Misfolding, Functional Amyloid, and Human Disease
TL;DR: The relative importance of the common main-chain and side-chain interactions in determining the propensities of proteins to aggregate is discussed and some of the evidence that the oligomeric fibril precursors are the primary origins of pathological behavior is described.
Journal ArticleDOI
Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism
Tohru Kitada,Shuichi Asakawa,Nobutaka Hattori,Hiroto Matsumine,Yasuhiro Yamamura,Shinsei Minoshima,Masayuki Yokochi,Yoshikuni Mizuno,Nobuyoshi Shimizu +8 more
TL;DR: Mutations in the newly identified gene appear to be responsible for the pathogenesis of Autosomal recessive juvenile parkinsonism, and the protein product is named ‘Parkin’.
Journal ArticleDOI
The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation
Peter Walter,David Ron +1 more
TL;DR: The vast majority of proteins that a cell secretes or displays on its surface first enter the endoplasmic reticulum, where they fold and assemble, and only properly assembled proteins advance from the ER to the cell surface.
Journal ArticleDOI
Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice
Taichi Hara,Kenji Nakamura,Makoto Matsui,Makoto Matsui,Makoto Matsui,Akitsugu Yamamoto,Yohko Nakahara,Rika Suzuki-Migishima,Minesuke Yokoyama,Kenji Mishima,Ichiro Saito,Hideyuki Okano,Noboru Mizushima +12 more
TL;DR: The results suggest that the continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration.