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Mutational analysis implicates the amyloid fibril as the toxic entity in Huntington's disease
Kenneth W Drombosky1, Sascha Rode2, Ravi Kodali2
1Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA; Graduate Program in Molecular Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Institute for Neurodegenerative Diseases (PIND), University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Neurobiology of Disease
|September 2, 2018
Summary
Huntington disease (HD) toxicity stems from huntingtin (htt) exon1 aggregation, not just polyglutamine (polyQ) length. Engineered htt analogs reveal amyloid formation drives toxicity, offering therapeutic targets.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Huntington disease (HD) is linked to expanded polyglutamine (polyQ) in huntingtin (htt) exon1.
- The exact toxic species (misfolded monomer, oligomer, or amyloid fibril) in HD pathogenesis remains debated.
Purpose of the Study:
- To investigate the role of htt exon1 aggregation propensity versus polyQ length in HD toxicity.
- To develop engineered htt exon1 analogs as tools to study polyQ self-assembly and toxicity.
Main Methods:
- Engineering htt exon1 analogs with varying polyQ lengths and aggregation properties.
- Assessing toxicity in rat neurons and Drosophila models.
- Evaluating the in vitro and in vivo effects of non-toxic oligomer-forming analogs on amyloid formation and toxicity.
Main Results:
- Engineered htt exon1 with short polyQ formed amyloid fibrils and induced HD-like toxicity.
- Modified analogs forming only spherical oligomers were non-toxic.
- Non-toxic analogs suppressed amyloid formation and rescued neurons/flies from mhtt exon1 toxicity.
Conclusions:
- Huntingtin exon1 aggregation propensity, particularly amyloid formation, is a more accurate predictor of toxicity than polyQ repeat length in HD models.
- Amyloid-related aggregates appear most toxic in these experimental systems.
- Engineered analogs serve as valuable tools for studying polyQ diseases and developing potential therapeutics.