Inhibition of mitochondrial fragmentation diminishes Huntington's disease-associated neurodegeneration.
J Clin Invest
; 123(12): 5371-88, 2013 Dec.
Article
em En
| MEDLINE
| ID: mdl-24231356
ABSTRACT
Huntington's disease (HD) is the result of expression of a mutated Huntingtin protein (mtHtt), and is associated with a variety of cellular dysfunctions including excessive mitochondrial fission. Here, we tested whether inhibition of excessive mitochondrial fission prevents mtHtt-induced pathology. We developed a selective inhibitor (P110-TAT) of the mitochondrial fission protein dynamin-related protein 1 (DRP1). We found that P110-TAT inhibited mtHtt-induced excessive mitochondrial fragmentation, improved mitochondrial function, and increased cell viability in HD cell culture models. P110-TAT treatment of fibroblasts from patients with HD and patients with HD with iPS cell-derived neurons reduced mitochondrial fragmentation and corrected mitochondrial dysfunction. P110-TAT treatment also reduced the extent of neurite shortening and cell death in iPS cell-derived neurons in patients with HD. Moreover, treatment of HD transgenic mice with P110-TAT reduced mitochondrial dysfunction, motor deficits, neuropathology, and mortality. We found that p53, a stress gene involved in HD pathogenesis, binds to DRP1 and mediates DRP1-induced mitochondrial and neuronal damage. Furthermore, P110-TAT treatment suppressed mtHtt-induced association of p53 with mitochondria in multiple HD models. These data indicate that inhibition of DRP1-dependent excessive mitochondrial fission with a P110-TAT-like inhibitor may prevent or slow the progression of HD.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Doença de Huntington
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Proteínas Mitocondriais
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Dinaminas
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GTP Fosfo-Hidrolases
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Proteínas Associadas aos Microtúbulos
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Mitocôndrias
Tipo de estudo:
Risk_factors_studies
Limite:
Adult
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Animals
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Child
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Humans
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Male
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article