Journal of neuroscience research
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Patients with Huntington's disease have an expanded polyglutamine tract in huntingtin and suffer severe brain atrophy and neurodegeneration. Because membrane dysfunction can occur in Huntington's disease, we addressed whether mutant huntingtin in brain and primary neurons is present in lipid rafts, which are cholesterol-enriched membrane domains that mediate growth and survival signals. Biochemical analysis of detergent-resistant membranes from brains and primary neurons of wild-type and presymptomatic Huntington's disease knock-in mice showed that wild-type and mutant huntingtin were recovered in lipid raft-enriched detergent-resistant membranes. ⋯ Increases in glycogen synthase kinase 3-beta have been associated with apoptotic cell death. Treating Huntington's disease primary neurons with inhibitors of glycogen synthase kinase 3-beta reduced neuronal death. We speculate that accumulation of mutant huntingtin and glycogen synthase kinase 3-beta in lipid rafts of presymptomatic Huntington's disease mouse neurons contributes to neurodegeneration in Huntington's disease.
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Deletions or mutations in survival of motor neuron 1 (SMN1) cause motor neuron loss and spinal muscular atrophy (SMA), a neuromuscular disorder, with the most severe type manifesting in utero. Whether SMA is a disease of defects in neurodevelopment and/or neuromaintenance remains unclear. We performed an analysis of Smn gene and protein expression during murine embryogenesis. ⋯ By comparison, Hif3a alternative splicing was affected only at the end stage of disease. This result suggests that alterations in mRNA splicing in SMA occur, in part, as a result of disease progression. Overall, we conclude that Smn depletion affects developmental processes, which ultimately may also contribute to SMA pathogenesis.