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 was associated with elevated death rates. Proteomic analysis indicated that cellular reactions to mHtt expression were weaker in cells expressing the lysineless protein, possibly implying a reduced capacity to cope with the proteotoxic stress. Taken together, the findings suggest a novel role for ubiquitination-attenuation of the pathogenic effect of mHtt.
Highlights
Huntington’s disease (HD) is a progressive incurable neurodegenerative disorder characterized by motor and neuropsychiatric symptoms
To measure the ubiquitination profile of mutant Htt (mHtt) in BACHD animals which fully display HD-like deficits, brain sections of 15-mo-old BACHD rats were subjected to proteomic analysis and compared to tissue samples collected in agematched WT rats
We found that lysine residues 6 and 9 in the N-terminal domain of mHtt are highly ubiquitinated in both the cortical and the striatal tissues, in striking contrast to the homologous two lysine residues in WT Htt that were not (Fig. 1 B and C)
Summary
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. 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 Expression of this form of mHtt was associated with elevated death rates. The hallmark of neurodegenerative disorders (e.g., Alzheimer’s, Parkinson’s, and Huntington’s disease) is the generation of aggregated proteins in different brain regions These large aggregates originate from smaller, invisible, and soluble oligomers/aggregates and are believed to be sequestered from essential cellular machineries and, to attenuate/postpone the pathologic process. Abolishing its ubiquitination results in generation of numerous smaller and less visible aggregates that are harmful to cells
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