Abstract
Huntington disease is a neurodegenerative disorder caused by an expanded polyglutamine (polyQ) repeat within the protein huntingtin (Htt). N-terminal fragments of the mutant Htt (mHtt) proteins containing the polyQ repeat are aggregation-prone and form intracellular inclusion bodies. Improving the clearance of mHtt fragments by intracellular degradation pathways is relevant to obviate toxic mHtt species and subsequent neurodegeneration. Because the proteasomal degradation pathway has been the subject of controversy regarding the processing of expanded polyQ repeats, we examined whether the proteasome can efficiently degrade Htt-exon1 with an expanded polyQ stretch both in neuronal cells and in vitro. Upon targeting mHtt-exon1 to the proteasome, rapid and complete clearance of mHtt-exon1 was observed. Proteasomal degradation of mHtt-exon1 was devoid of polyQ peptides as partial cleavage products by incomplete proteolysis, indicating that mammalian proteasomes are capable of efficiently degrading expanded polyQ sequences without an inhibitory effect on the proteasomal activity.
Highlights
Huntington disease is caused by an expanded polyglutamine repeat within the protein huntingtin
MHtt-exon1 Is Degraded by Macroautophagy and the Proteasome—To determine whether macroautophagy and the proteasome are involved in mutant Htt (mHtt)-exon1 degradation, mHtt-exon197Q was expressed for 24 h in Neuro-2a cells treated with the proteasomal inhibitor epoxomicin or the autophagy inhibitor 3-MA for the last 16 h of expression
To analyze whether the cellular proteasome is capable of cleaving within an expanded polyQ stretch, considering the native Httexon1 protein context, we targeted the mHtt-exon1 protein to the proteasomal pathway in ubiquitin-dependent and -independent manners by the fusion of mHtt-exon1 to various degron signals
Summary
Huntington disease is caused by an expanded polyglutamine repeat within the protein huntingtin. Huntington disease is a neurodegenerative disorder caused by an expanded polyglutamine (polyQ) repeat within the protein huntingtin (Htt). N-terminal fragments of the mutant Htt (mHtt) proteins containing the polyQ repeat are aggregationprone and form intracellular inclusion bodies. Huntington disease (HD) is a neurodegenerative disorder caused by a polyglutamine (polyQ) repeat expansion in the respective protein huntingtin (Htt) [1, 2]. N-terminal fragments of mutant Htt (mHtt) protein containing the expanded polyQ tract are highly prone to aggregate and form intracellular inclusion bodies (IBs), as observed in human HD post-mortem brain and in animal or cellular systems (8 –12). Disappearance of IBs and an amelioration of disease phenotype are observed after shutdown of mHtt expression in a conditional HD mouse model, suggesting that autophagy can remove aggregated mHtt, and HD may be reversible [21]. Mammalian proteasomes are capable of degrading expanded polyQ sequences, and proteasomal activity is not affected by the presence of mHtt-exon
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