Protein misfolding and aggregation have been recognized as a common molecular pathogenesis of various neurodegenerative diseases including Alzheimer's, Parkinson's, and the polyglutamine (polyQ) diseases. The polyQ diseases, including Huntington's disease and various spinocerebellar ataxias, are caused by abnormal expansions of the polyQ stretch (>35-40) within disease-causative proteins. Recently, defects in protein degradation in the brain have been shown to cause neurodegeneration in genetically-engineered mice, highlighting two important roles of protein degradation systems in neurodegenerative diseases; 1) their dysfunction in the pathogenesis and 2) their activation as a therapy. However, it is indispensable to eliminate only the pathogenic proteins to avoid deleterious side effects. Aiming to selectively degrade the expanded polyQ proteins, we employed QBP1, a peptide which specifically binds to the expanded polyQ stretch. We designed a chimeric protein with the Hsc70 binding motif, a signal sequence for chaperone-mediated autophagy, fused to QBP1 (Hsc70BM-QBP1), and found that Hsc70BM-QBP1 accelerates the selective degradation of expanded polyQ proteins in cell culture. Gene therapy using a viral vector expressing Hsc70BM-QBP1 effectively ameliorates the motor dysfunction and premature death in polyQ disease model mice. We propose that our therapeutic strategy to selectively degrade the pathogenic proteins can also be applied to other neurodegenerative diseases.