Affiliations: Amsterdam UMC, University of Amsterdam, Medical Biology, Meibergdreef, Amsterdam, Netherlands
Correspondence:
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Correspondence to: Eric A.J. Reits, Amsterdam UMC location University of Amsterdam, Medical Biology, Meibergdreef 9, Amsterdam, The Netherlands. Tel.: +31 0 20 566 6259; E-mail: e.a.reits@amsterdamumc.nl.
Abstract: Background:Huntington’s disease is an inheritable autosomal dominant disorder caused by an expanded CAG trinucleotide repeat within the Huntingtin gene, leading to a polyglutamine (polyQ) expansion in the mutant protein. Objective:A potential therapeutic approach for delaying or preventing the onset of the disease involves enhancing the degradation of the aggregation-prone polyQ-expanded N-terminal mutant huntingtin (mHTT) exon1 fragment. A few proteases and peptidases have been identified that are able to cleave polyQ fragments with low efficiency. This study aims to identify a potent polyQ-degrading endopeptidase. Methods:Here we used quenched polyQ peptides to identify a polyQ-degrading endopeptidase. Next we investigated its role on HTT turnover, using purified polyQ-expanded HTT fragments and striatal cells expressing mHTT exon1 peptides. Results:We identified insulin-degrading enzyme (IDE) as a novel endopeptidase for degrading polyQ peptides. IDE was, however, ineffective in reducing purified polyQ-expanded HTT fragments. Similarly, in striatal cells expressing mHTT exon1 peptides, IDE did not enhance mHTT turnover. Conclusions:This study shows that despite IDE’s efficiency in degrading polyQ peptides, it does not contribute to the direct degradation of polyQ-expanded mHTT fragments.
Keywords: Huntington’s disease, huntingtin protein, insulysin, IDE protein, protein aggregates
