RESUMO
Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine tract in the huntingtin (HTT) protein. Mutant HTT (mHTT) toxicity is caused by its aggregation/oligomerization. The striatum is the most vulnerable region, although all brain regions undergo neuronal degeneration in the disease. Here we show that the levels of Bim, a BH3-only protein, are significantly increased in HD human post-mortem and HD mouse striata, correlating with neuronal death. Bim reduction ameliorates mHTT neurotoxicity in HD cells. In the HD mouse model, heterozygous Bim knockout significantly mitigates mHTT accumulation and neuronal death, ameliorating disease-associated phenotypes and lifespan. Therefore, Bim could contribute to the progression of HD.
Assuntos
Proteína 11 Semelhante a Bcl-2/metabolismo , Corpo Estriado/metabolismo , Proteína Huntingtina/genética , Doença de Huntington/metabolismo , Neurônios/patologia , Idoso , Animais , Proteína 11 Semelhante a Bcl-2/genética , Corpo Estriado/patologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Técnicas de Inativação de Genes , Heterozigoto , Humanos , Proteína Huntingtina/metabolismo , Doença de Huntington/genética , Doença de Huntington/mortalidade , Doença de Huntington/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Neurônios/metabolismo , Fenótipo , Agregados Proteicos/genética , RNA Interferente PequenoRESUMO
Autophagy cargo recognition and clearance are essential for intracellular protein quality control. SQSTM1/p62 sequesters intracellular aberrant proteins and mediates cargo delivery for their selective autophagic degradation. The formation of p62 non-membrane-bound liquid compartments is critical for its function as a cargo receptor. The regulation of p62 phase separation/condensation has yet been poorly characterised. Using an unbiased yeast two-hybrid screening and complementary approaches, we found that DAXX physically interacts with p62. Cytoplasmic DAXX promotes p62 puncta formation. We further elucidate that DAXX drives p62 liquid phase condensation by inducing p62 oligomerisation. This effect promotes p62 recruitment of Keap1 and subsequent Nrf2-mediated stress response. The present study suggests a mechanism of p62 phase condensation by a protein interaction, and indicates that DAXX regulates redox homoeostasis, providing a mechanistic insight into the prosurvival function of DAXX.
