Mutant protein in Huntington disease is resistant to proteolysis in affected brain.
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.
Dyer
R B
RB
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
McMurray
C T
CT
D000368:Aged; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D002850:Chromatography, Gel; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism* / Q000633:toxicity; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism* / Q000633:toxicity; D009928:Organ Specificity; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D012995:Solubility; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases