Control of the structural landscape and neuronal proteotoxicity of mutant Huntingtin by domains flanking the polyQ tract
- Stanford University, United States
- Sanofi R&D, France
- Miltenyi Biotec, Germany
- Baylor College of Medicine, United States
- Paul Scherrer Institute, Switzerland
- Duke University Medical Center, United States
Abstract
Many neurodegenerative diseases are linked to amyloid aggregation. In Huntington's disease (HD), neurotoxicity correlates with increased aggregation propensity of a polyglutamine (polyQ) expansion in exon 1 of mutant huntingtin protein (mHtt). Here we establish how the domains flanking the polyQ tract shape the mHtt conformational landscape in vitro and in neurons. In vitro, the flanking domains have opposing effects on the conformation and stabilities of oligomers and amyloid fibrils. The N-terminal N17 promotes amyloid fibril formation, while the C-terminal Proline Rich Domain destabilizes fibrils and enhances oligomer formation. However, in neurons both domains act synergistically to engage protective chaperone and degradation pathways promoting mHtt proteostasis. Surprisingly, when proteotoxicity was assessed in rat corticostriatal brain slices, either flanking region alone sufficed to generate a neurotoxic conformation, while the polyQ tract alone exhibited minimal toxicity. Linking mHtt structural properties to its neuronal proteostasis should inform new strategies for neuroprotection in polyQ-expansion diseases.
Article and author information
Author details
Funding
National Institute of General Medical Sciences (gm56433)
- Koning Shen
- Judith Frydman
National Institute of Neurological Disorders and Stroke (NS080514)
- Barbara Calamini
- Donald C Lo
NIH Office of the Director (pn2ey016525)
- Sarah H Shahmoradian
- Wah Chiu
- Judith Frydman
National Institute of General Medical Sciences (gm103832)
- Boxue Ma
- Sarah H Shahmoradian
- Wah Chiu
ellison medical foundation
- Jonathan A Fauerbach
- Judith Frydman
National Institute of Neurological Disorders and Stroke (NS092525)
- Koning Shen
- Judith Frydman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: No human subjects. Animals were handled and killed in accordance with NIH guidelines and under approval and oversight of the Duke University institutional animal care and use committee (IACUC) to Don Lo. Protocol number A147-14-06.
Copyright
© 2016, Shen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Control of the structural landscape and neuronal proteotoxicity of mutant Huntingtin by domains flanking the polyQ tract
eLife 5:e18065.
https://doi.org/10.7554/eLife.18065
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