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Mol Neurobiol ; 58(6): 2704-2723, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33492644

RESUMO

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expansion of polyglutamine stretch (polyQ) at the N-terminus of huntingtin (Htt) protein. The abnormally expanded polyQ stretch of mutant Htt makes it prone to aggregate, leading to neuropathology. HAP40 is a 40-kDa huntingtin-associated protein with undefined functions. HAP40 protein has been shown to increase in HD patients and HD mouse model cells. However, recent proteomic analysis provides new evidence that HAP40 protein is decreased in the striatum of HD knockin model mice. In this study, we developed HAP40-specific antibody and showed that both HAP40 mRNA and its encoded protein were reduced in HD striatal neuronal STHDHQ111/Q111 cells. Depletion of endogenous HAP40 led to cytotoxicity that was linked to increased accumulation of aggregated and soluble forms of mutant Htt, which recapitulates HD pathology. Moreover, we found that HAP40 depletion reduced the proteasomal chymotrypsin-like activity and increased the autophagic flux. Importantly, inhibition of p38 MAPK pathway by PD169316 increased chymotrypsin-like activity and reduced accumulation of aggregated and soluble forms of mutant Htt in HAP40-depleted cells to alleviate HAP40-depletion induced cytotoxicity. Taken together, our results suggest that modulation of p38 MAPK-mediated proteasomal peptidase activity may provide a new therapeutic target to restore proteostasis in neurodegenerative diseases.


Assuntos
Doença de Huntington/enzimologia , Doença de Huntington/patologia , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular , Quimotripsina/metabolismo , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Modelos Animais de Doenças , Proteínas de Fluorescência Verde/metabolismo , Proteína Huntingtina/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Proteínas Mutantes/metabolismo , Agregados Proteicos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Subunidades Proteicas/metabolismo , Solubilidade , Ubiquitina/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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