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09:06
Growth Assays to Assess Polyglutamine Toxicity in Yeast
Published on: March 5, 2012
Prefoldin protects neuronal cells from polyglutamine toxicity by preventing aggregation formation
Erika Tashiro1, Tamotsu Zako, Hideki Muto
1Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, USA.
The Journal of Biological Chemistry
|May 31, 2013
Summary
Prefoldin prevents Huntington disease (HD) protein aggregation. Disrupting prefoldin increases toxic soluble protein oligomers, leading to cell death, suggesting these oligomers are more harmful than larger aggregates.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Huntington disease (HD) arises from expanded polyglutamine (polyQ) tracts in the huntingtin (HTT) gene, leading to cell death.
- Prefoldin is a molecular chaperone (PFD1-6) that assists in nascent polypeptide folding.
Purpose of the Study:
- To investigate the role of prefoldin in the aggregation of pathogenic huntingtin protein (HTT) and its relation to cell death in Huntington disease.
Main Methods:
- Knockdown of prefoldin subunits (PFD2, PFD5) in cells expressing mutant HTT.
- Analysis of HTT aggregate formation, cell death, and soluble oligomer size using fluorescence correlation spectroscopy.
- In vitro single-molecule observation of HTT aggregation.
Main Results:
- Knockdown of PFD2 and PFD5 disrupted prefoldin, causing pathogenic HTT aggregation and cell death.
- Cell death occurred without HTT inclusions; soluble HTT oligomers increased in size.
- Prefoldin suppressed HTT aggregation at the early dimer to tetramer stage in vitro.
Conclusions:
- Prefoldin inhibits the elongation of pathogenic HTT oligomers, preventing inclusion formation.
- Soluble oligomers of polyQ-expanded HTT are more cytotoxic than larger inclusions.
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