In vivo study of the role of the chaperone HSP110 in amyloid beta (Aβ) aggregation
Date Issued
2024-06-19
Author(s)
Supervisors
Referees
Abstract
Protein misfolding and aggregation are characteristic events in most neurodegenerative diseases. To prevent proteotoxicity, the cell has evolved a protein homeostasis (proteostasis) network comprised of molecular chaperones and proteolytic pathways. Molecular chaperones can regulate protein folding by e.g. prevention of protein aggregation, refolding of proteins and protein disaggregation. Molecular chaperones can be used as targets for pharmacological intervention against neurodegenerative diseases. HSP110 is a poorly characterised molecular chaperone and its functional spectrum is not yet fully elucidated. Nevertheless, HSP110 has recently been implicated in various neurodegenerative diseases, including Alzheimer´s disease (AD). Aggregation of the amyloid beta peptide (Aβ) is one of the hallmarks of AD. In vitro studies have shown that human HSP110 can inhibit Aβ1-42 fibril formation either alone or in combination with HSC70 and a J-domain protein. However, the beneficial versus detrimental implications of HSP110 in neurodegenerative physiological contexts are still under debate.
Therefore, I investigated the effect of HSP-110 and its interplay with Aβ1-42 in vivo using C. elegans as a model organism. I generated a novel C. elegans model that overexpressed hsp-110 pan-neuronally and I also depleted hsp-110 by RNAi-mediated knockdown. I analyzed the role of HSP-110 in Aβ1-42 aggregation using a pan-neuronal Aβ C. elegans model. In addition, I performed transcriptomic and proteomic analyses of pan-neuronal and muscular Aβ C. elegans strains to reveal global changes in gene expression and protein levels in these AD models. I could show that hsp-110 overexpression exacerbated Aβ1-42 aggregation in vivo. Conversely, hsp-110 depletion reduced Aβ1-42 aggregation significantly in the IL2 neurons, which mark the onset of Aβ1-42 aggregation in C. elegans. Moreover, HSP-110 is a modulator of the autophagy pathway, with overexpression of hsp-110 impairing and depletion of hsp-110 inducing autophagy. HSP-110 appears to regulate multiple nodes of the proteostasis network and further studies are necessary to fully unravel the effect on Aβ1-42. In addition, I gained a preliminary understanding of the biological changes associated with Aβ1-42 aggregation in C. elegans using transcriptomic and proteomic analyses. Surprisingly, of the molecular chaperones, only small HSPs showed an increased abundance.
Therefore, I investigated the effect of HSP-110 and its interplay with Aβ1-42 in vivo using C. elegans as a model organism. I generated a novel C. elegans model that overexpressed hsp-110 pan-neuronally and I also depleted hsp-110 by RNAi-mediated knockdown. I analyzed the role of HSP-110 in Aβ1-42 aggregation using a pan-neuronal Aβ C. elegans model. In addition, I performed transcriptomic and proteomic analyses of pan-neuronal and muscular Aβ C. elegans strains to reveal global changes in gene expression and protein levels in these AD models. I could show that hsp-110 overexpression exacerbated Aβ1-42 aggregation in vivo. Conversely, hsp-110 depletion reduced Aβ1-42 aggregation significantly in the IL2 neurons, which mark the onset of Aβ1-42 aggregation in C. elegans. Moreover, HSP-110 is a modulator of the autophagy pathway, with overexpression of hsp-110 impairing and depletion of hsp-110 inducing autophagy. HSP-110 appears to regulate multiple nodes of the proteostasis network and further studies are necessary to fully unravel the effect on Aβ1-42. In addition, I gained a preliminary understanding of the biological changes associated with Aβ1-42 aggregation in C. elegans using transcriptomic and proteomic analyses. Surprisingly, of the molecular chaperones, only small HSPs showed an increased abundance.
Subjects
Amyloid beta
;
Alzheimer´s disease
;
chaperone, HSP110
;
C.elegans
;
protein aggregation
Institution
Type
Dissertation
Language
English
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PhD thesis_Montresor.pdf
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