Generalized brain and skin proteasome inhibition in Huntington's disease

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Abstract
Mutated intracellular huntingtin is widely expressed in tissues of Huntington's disease (HD) patients. Intraneuronal nuclear protein aggregates of mutant huntingtin are present in HD brains, suggesting a dysfunction of the ubiquitin proteasome system (UPS). Because many cells and tissues can cope with the abnormal gene effects while others dysfunction and die, we determined gene‐induced effects and considered the hypothesis that the gene causes multiple intracellular problems, but severe pathology is seen only in selected brain regions. In this study, we found inhibition of UPS function in both early (0–1, with no or little neuronal loss) and late (3–4, with more severe neuronal loss) stage HD patients' cerebellum, cortex, substantia nigra and caudate‐putamen brain regions. Late HD stage increases in ubiquitin levels were unique to caudate‐putamen. HD patients' skin fibroblasts also had UPS inhibition similar to brain despite increases in proteasome β‐subunit expression. Gene delivery and expression of proteasome activator PA28 increased UPS function in normal but not HD fibroblasts. These generalized UPS problems are associated with severe neuronal pathology only when coupled with decreases in brain‐derived neurotrophic factor levels, mitochondrial complex II/III activity, and increases of ubiquitin levels particularly as seen in the caudate‐putamen of HD patients. Ann Neurol 2004