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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.

SUBMITTER: Li C 

PROVIDER: S-EPMC10625127 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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A Specific Mini-Intrabody Mediates Lysosome Degradation of Mutant Huntingtin.

Li Caijuan C   Lin Yingqi Y   Chen Yizhi Y   Song Xichen X   Zheng Xiao X   Li Jiawei J   He Jun J   Chen Xiusheng X   Huang Chunhui C   Wang Wei W   Wu Jianhao J   Wu Jiaxi J   Gao Jiale J   Tu Zhuchi Z   Li Xiao-Jiang XJ   Yan Sen S   Li Shihua S  

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20230908 31


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 tha  ...[more]

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