A Specific Mini‐Intrabody Mediates Lysosome Degradation of Mutant Huntingtin

Abstract

Accumulation of misfolded proteins leads to many neurodegenerative diseases that can be treated by lowering or removing mutant proteins. Huntington's disease (HD) is characterized by the intracellular accumulation of mutant huntingtin (mHTT) that can be soluble and aggregated in the central nervous system and causes neuronal damage and death. Here, an intracellular antibody (intrabody) fragment is generated that can specifically bind mHTT and link to the lysosome for degradation. It is found that delivery of this peptide by either brain injection or intravenous administration can efficiently clear the soluble and aggregated mHTT by activating the lysosomal degradation pathway, resulting in amelioration of gliosis and dyskinesia in HD knock‐in (KI‐140Q) mice. These findings suggest that the small intrabody peptide linked to lysosomes can effectively lower mutant proteins and provide a new approach for treating neurodegenerative diseases that are caused by the accumulation of mutant proteins.

Huntington’s Disease: Complex Pathogenesis and Therapeutic Strategies

“…Additionally, SM3 can alleviate abnormal behaviors in HD KI-140Q mice by enhancing lysosomal degradation activity. Intravenous administration of SM3 effectively reduces soluble and insoluble mHTT in the brains of HD KI-140Q mice, improving HD-related neuropathology and motor function deficits [178].…”