A toxic mutant huntingtin species is resistant to selective autophagy

• Published in: Nature chemical biology Vol. 13; no. 11; pp. 1152 - 1154
• Main Authors: Fu, Yuhua, Wu, Peng, Pan, Yuyin, Sun, Xiaoli, Yang, Huiya, Difiglia, Marian, Lu, Boxun
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2017; Nature Publishing Group
• Subjects: 13/89; 14; 14/34; 631/378/340; 631/45/612; 631/80/470; 64/60; 692/699/375; 82/1; 96/33; Autophagy; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Brain - metabolism; Brain - pathology; brief-communication; Cell Biology; Cells, Cultured; Chemistry; Chemistry/Food Science; Fibroblasts - metabolism; Fibroblasts - pathology; Humans; Huntingtin; Huntingtin Protein - genetics; Huntingtin Protein - metabolism; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington Disease - pathology; Huntington's disease; Mutation; Neurodegeneration; Neurodegenerative diseases; Peptides - genetics; Phagocytosis; Polyglutamine; Polyubiquitin - metabolism; Protein Conformation; Protein folding; Proteolysis; Repetitive Sequences, Nucleic Acid; Toxicity; Trinucleotide repeat diseases; Ubiquitination
• ISSN: 1552-4450; 1552-4469; 1552-4469
• DOI: 10.1038/nchembio.2461

A toxic conformation of disease-linked huntingtin protein with expanded polyQ is degraded more slowly than the other conformations, as it is less able to engage the autophagy machinery, explaining its higher toxicity compared to other conformations. Protein misfolding is a common theme in neurodegenerative disorders including Huntington's disease (HD). The HD-causing mutant huntingtin protein (mHTT) has an expanded polyglutamine (polyQ) stretch that may adopt multiple conformations, and the most toxic of these is the one recognized by antibody 3B5H10. Here we show that the 3B5H10-recognized mHTT species has a slower degradation rate due to its resistance to selective autophagy in human cells and brains, revealing mechanisms of its higher toxicity.