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Sci Rep. 2018 Jun 22;8(1):9554. doi: 10.1038/s41598-018-27900-5.

Comparative Analysis of Mutant Huntingtin Binding Partners in Yeast Species.

Author information

1
Departments of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire, 03755, United States.
2
Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire, 03755, United States.
3
Department of Pathology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada.
4
Biomedical Data Sciences, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire, 03755, United States.
5
Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire, 03755, United States. Supattapone@dartmouth.edu.
6
Medicine, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire, 03755, United States. Supattapone@dartmouth.edu.

Abstract

Huntington's disease is caused by the pathological expansion of a polyglutamine (polyQ) stretch in Huntingtin (Htt), but the molecular mechanisms by which polyQ expansion in Htt causes toxicity in selective neuronal populations remain poorly understood. Interestingly, heterologous expression of expanded polyQ Htt is toxic in Saccharomyces cerevisiae cells, but has no effect in Schizosaccharomyces pombe, a related yeast species possessing very few endogenous polyQ or Q/N-rich proteins. Here, we used a comprehensive and unbiased mass spectrometric approach to identify proteins that bind Htt in a length-dependent manner in both species. Analysis of the expanded polyQ-associated proteins reveals marked enrichment of proteins that are localized to and play functional roles in nucleoli and mitochondria in S. cerevisiae, but not in S. pombe. Moreover, expanded polyQ Htt appears to interact preferentially with endogenous polyQ and Q/N-rich proteins, which are rare in S. pombe, as well as proteins containing coiled-coil motifs in S. cerevisiae. Taken together, these results suggest that polyQ expansion of Htt may cause cellular toxicity in S. cerevisiae by sequestering endogenous polyQ and Q/N-rich proteins, particularly within nucleoli and mitochondria.

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