Suppression of neuropil aggregates and neurological symptoms by an intracellular antibody implicates the cytoplasmic toxicity of mutant huntingtin
Year: 2008
Type: article
Abstract: 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.
Source: The Journal of Cell Biology
Authors: Chuan-En Wang, Hui Zhou, John R. McGuire, Vincenzo Cerullo, Brendan Lee, Shi-Hua Li, Xiao-Jiang Li
Institutions: Emory University, Baylor College of Medicine
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: Synaptic toxicity of Huntington disease protein, G2354173201, G2373276806, G2782159433, Neuronal function of huntingtin-associated protein, G4752896000, Polyglutamine expansion and neuropathology, G5317928879, G5337012820, G5634783806, Blocking Huntingtin Toxicity by Intrabody, G7338642570, G9000237978
OpenAlex ID: W2145386709