Suppression of neuropil aggregates and neurological symptoms by an intracellular antibody implicates the cytoplasmic toxicity of mutant huntingtin.
Mutant huntingtin accumulates in the neuronal nuclei and processes, which suggests that its subcellular localization is critical for the pathology of Huntington's disease (HD). However, the contribution of cytoplasmic mutant huntingtin and its aggregates in neuronal processes (neuropil aggregates) has not been rigorously explored. We generated an intracellular antibody (intrabody) whose binding to a unique epitope of human huntingtin is enhanced by polyglutamine expansion. This intrabody decreases the cytotoxicity of mutant huntingtin and its distribution in neuronal processes. When expressed in the striatum of HD mice via adenoviral infection, the intrabody reduces neuropil aggregate formation and ameliorates neurological symptoms. Interaction of the intrabody with mutant huntingtin increases the ubiquitination of cytoplasmic huntingtin and its degradation. These findings suggest that the intrabody reduces the specific neurotoxicity of cytoplasmic mutant huntingtin and its associated neurological symptoms by preventing the accumulation of mutant huntingtin in neuronal processes and promoting its clearance in the cytoplasm.
Wang
Chuan-En
CE
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Zhou
Hui
H
McGuire
John R
JR
Cerullo
Vincenzo
V
Lee
Brendan
B
Li
Shi-Hua
SH
Li
Xiao-Jiang
XJ
D000256:Adenoviridae / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D003593:Cytoplasm / Q000378:metabolism*; D000939:Epitopes / Q000737:chemistry; D006801:Humans; D000071058:Huntingtin Protein; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics*; D009422:Nervous System Diseases / Q000473:pathology; D019581:Neuropil / Q000737:chemistry*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
D000911:Antibodies, Monoclonal; D000939:Epitopes; C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins