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Updated: Jul 13, 2026

Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Mutant protein in Huntington disease is resistant to proteolysis in affected brain
1Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Abstract:
The cause of Huntington disease pathophysiology is unknown, but a major hypothesis suggests that toxicity arises from the cleavage and accumulation of amino-terminal fragments containing an expanded polyglutamine region. In evaluating huntingtin protein (HD) from human brain, transgenic animals and cells, we observed, unexpectedly, that mutant HD is more resistant to proteolysis than normal HD. The N-terminal cleavage fragments we observed arise from the processing of normal HD and are sequestered by full-length mutant HD. Our results support a model in which inhibition of proteolysis of mutant HD leads to aggregation and toxicity through the sequestering of important targets, including normal HD.
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