Linking the conformational landscape of Huntingtin to proteostasis and neurotoxicity in Huntington's disease
- Amyloid aggregation is one of the main hallmarks of neurodegenerative diseases. However, what triggers this amyloid aggregation and how it results to toxicity are unclear. In Huntington's disease (HD), neurodegeneration correlates with the amyloid aggregation of a mutant protein Huntingtin (Htt). This mutation is an expansion of a polyQ repeat in the Htt protein. While the length of the polyQ repeat has been shown to correlate with severity of neurodegeneration in HD, recent studies have highlighted how regions flanking the polyQ repeat alter Htt aggregation and toxicity in various models. In this work, we investigate the roles the polyQ flanking regions play in controlling complex interplay between the biophysics and cell biology leading to the cellular fate mHtt. We find that these polyQ flanking regions impact the energetics, conformations and fibrillar structure of the Htt protein. Importantly, the impact of these polyQ flanking regions have on the Htt conformational landscape have direct consequences on neuronal toxicity and cellular proteostasis of mutant Htt. Overall, our study provides, for the first time, an integrated view of how the biophysical properties of an amyloidogenic protein are linked to their behavior in the cell. Our work linking the mHtt conformational landscape with neuronal proteostasis and toxicity informs rational avenues to leverage the roles of the polyQ flanking regions for HD therapeutics.
|Type of resource
|electronic; electronic resource; remote
|1 online resource.
|Stanford University, Department of Biology.
|Gozani, Or Pinchas
|Gozani, Or Pinchas
|Statement of responsibility
|Submitted to the Department of Biology.
|Thesis (Ph.D.)--Stanford University, 2016.
- © 2016 by Koning Shen
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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