Expanded polyglutamine-containing N-terminal huntingtin fragments are entirely degraded by mammalian proteasomes

Abstract

Huntington diseaseisaneurodegenerative 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. 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 andin vitro. Upon targeting mHtt-exon1 tothe proteasome, rapid and complete clearance of mHtt-exon1 was observed. Proteasomal degradation of mHttexon1 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. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.