HSP110 is a modulator of amyloid beta (Aβ) aggregation and proteotoxicity.

Autor: Montresor S; Department of Cell Biology, University of Bremen, Bremen, Germany., Pigazzini ML; Leibniz Institute for Molecular Pharmacology, Berlin, Germany., Baskaran S; Leibniz Institute on Aging-Fritz-Lipmann-Institute, Jena, Germany., Sleiman M; Department of Cell Biology, University of Bremen, Bremen, Germany.; Leibniz Institute on Aging-Fritz-Lipmann-Institute, Jena, Germany., Adhikari G; Leibniz Institute on Aging-Fritz-Lipmann-Institute, Jena, Germany., Basilicata L; Department of Cell Biology, University of Bremen, Bremen, Germany., Secker L; Department of Cell Biology, University of Bremen, Bremen, Germany., Jacob N; Department of Cell Biology, University of Bremen, Bremen, Germany., Ehlert Y; Department of Cell Biology, University of Bremen, Bremen, Germany., Kelkar A; Department of Cell Biology, University of Bremen, Bremen, Germany., Kalsi GK; Department of Cell Biology, University of Bremen, Bremen, Germany., Kulkarni N; Department of Cell Biology, University of Bremen, Bremen, Germany., Spellerberg P; Department of Cell Biology, University of Bremen, Bremen, Germany., Kirstein J; Leibniz Institute on Aging-Fritz-Lipmann-Institute, Jena, Germany.; Friedrich-Schiller-Universität, Institute for Biochemistry & Biophysics, Jena, Germany.
Jazyk: angličtina
Zdroj: Journal of neurochemistry [J Neurochem] 2024 Aug 23. Date of Electronic Publication: 2024 Aug 23.
DOI: 10.1111/jnc.16214
Abstrakt: Chaperones safeguard protein homeostasis by promoting folding and preventing aggregation. HSP110 is a cytosolic chaperone that functions as a nucleotide exchange factor for the HSP70 cycle. Together with HSP70 and a J-domain protein (JDP), HSP110 maintains protein folding and resolubilizes aggregates. Interestingly, HSP110 is vital for the HSP70/110/JDP-mediated disaggregation of amyloidogenic proteins implicated in neurodegenerative diseases (i.e., α-synuclein, HTT, and tau). However, despite its abundance, HSP110 remains still an enigmatic chaperone, and its functional spectrum is not very well understood. Of note, the disaggregation activity of neurodegenerative disease-associated amyloid fibrils showed both beneficial and detrimental outcomes in vivo. To gain a more comprehensive understanding of the chaperone HSP110 in vivo, we analyzed its role in neuronal proteostasis and neurodegeneration in C. elegans. Specifically, we investigated the role of HSP110 in the regulation of amyloid beta peptide (Aβ) aggregation using an established Aβ-C. elegans model that mimics Alzheimer's disease pathology. We generated a novel C. elegans model that over-expresses hsp-110 pan-neuronally, and we also depleted hsp-110 by RNAi-mediated knockdown. We assessed Aβ aggregation in vivo and in situ by fluorescence lifetime imaging. We found that hsp-110 over-expression exacerbated Aβ aggregation and appeared to reduce the conformational variability of the Aβ aggregates, whereas hsp-110 depletion reduced aggregation more significantly in the IL2 neurons, which marked the onset of Aβ aggregation. HSP-110 also plays a central role in growth and fertility as its over-expression compromises nematode physiology. In addition, we found that HSP-110 modulation affects the autophagy pathway. While hsp-110 over-expression impairs the autophagic flux, a depletion enhances it. Thus, HSP-110 regulates multiple nodes of the proteostasis network to control amyloid protein aggregation, disaggregation, and autophagic clearance.
(© 2024 The Author(s). Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)
Databáze: MEDLINE
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