Site-specific ubiquitination of pathogenic huntingtin attenuates its deleterious effects

Proceedings of the National Academy of Sciences of the United States of America
Vicky Hakim-EshedAaron Ciechanover

Abstract

Huntington's disease (HD) is a progressive incurable neurodegenerative disorder characterized by motor and neuropsychiatric symptoms. It is caused by expansion of a cytosine-adenine-guanine triplet in the N-terminal domain of exon 1 in the huntingtin (HTT) gene that codes for an expanded polyglutamine stretch in the protein product which becomes aggregation prone. The mutant Htt (mHtt) aggregates are associated with components of the ubiquitin-proteasome system, suggesting that mHtt is marked for proteasomal degradation and that, for reasons still debated, are not properly degraded. We used a novel HD rat model, proteomic analysis, and long-term live neuronal imaging to characterize the effects of ubiquitination on aggregation of mHtt and subsequent cellular responses. We identified two lysine residues, 6 and 9, in the first exon of mHtt that are specifically ubiquitinated in striatal and cortical brain tissues of mHtt-transgenic animals. Expression of mHtt exon 1 lacking these ubiquitination sites in cortical neurons and cultured cells was found to slow aggregate appearance rates and reduce their size but at the same time increase the number of much smaller and less visible ones. Importantly, expression of this form of mHtt wa...Continue Reading

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Citations

Jul 18, 2020·Proceedings of the National Academy of Sciences of the United States of America·Vicky Hakim-EshedAaron Ciechanover
Jan 29, 2021·Frontiers in Molecular Neuroscience·Estibaliz Etxeberria-RekaldeBirgit Hutter-Paier

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