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DJ-1 is an essential downstream mediator in PINK1/parkin-dependent mitophagy.
Imberechts, Dorien; Kinnart, Inge; Wauters, Fieke; Terbeek, Joanne; Manders, Liselot; Wierda, Keimpe; Eggermont, Kristel; Madeiro, Rodrigo Furtado; Sue, Carolyn; Verfaillie, Catherine; Vandenberghe, Wim.
Afiliação
  • Imberechts D; Laboratory for Parkinson Research, KU Leuven, 3000 Leuven, Belgium.
  • Kinnart I; Laboratory for Parkinson Research, KU Leuven, 3000 Leuven, Belgium.
  • Wauters F; Laboratory for Parkinson Research, KU Leuven, 3000 Leuven, Belgium.
  • Terbeek J; Laboratory for Parkinson Research, KU Leuven, 3000 Leuven, Belgium.
  • Manders L; Laboratory for Parkinson Research, KU Leuven, 3000 Leuven, Belgium.
  • Wierda K; Electrophysiology Expertise Unit, VIB-KU Leuven Center for Brain and Disease Research, 3000 Leuven, Belgium.
  • Eggermont K; Stem Cell and Developmental Biology, KU Leuven, 3000 Leuven, Belgium.
  • Madeiro RF; Stem Cell and Developmental Biology, KU Leuven, 3000 Leuven, Belgium.
  • Sue C; Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St. Leonards 2065, Australia.
  • Verfaillie C; Stem Cell and Developmental Biology, KU Leuven, 3000 Leuven, Belgium.
  • Vandenberghe W; Laboratory for Parkinson Research, KU Leuven, 3000 Leuven, Belgium.
Brain ; 145(12): 4368-4384, 2022 12 19.
Article em En | MEDLINE | ID: mdl-36039535
ABSTRACT
Loss-of-function mutations in the PRKN, PINK1 and PARK7 genes (encoding parkin, PINK1 and DJ-1, respectively) cause autosomal recessive forms of Parkinson's disease. PINK1 and parkin jointly mediate selective autophagy of damaged mitochondria (mitophagy), but the mechanisms by which loss of DJ-1 induces Parkinson's disease are not well understood. Here, we investigated PINK1/parkin-mediated mitophagy in cultured human fibroblasts and induced pluripotent stem cell-derived neurons with homozygous PARK7 mutations. We found that DJ-1 is essential for PINK1/parkin-mediated mitophagy. Loss of DJ-1 did not interfere with PINK1 or parkin activation after mitochondrial depolarization but blocked mitophagy further downstream by inhibiting recruitment of the selective autophagy receptor optineurin to depolarized mitochondria. By contrast, starvation-induced, non-selective autophagy was not affected by loss of DJ-1. In wild-type fibroblasts and induced pluripotent stem cell-derived dopaminergic neurons, endogenous DJ-1 translocated to depolarized mitochondria in close proximity to optineurin. DJ-1 translocation to depolarized mitochondria was dependent on PINK1 and parkin and did not require oxidation of cysteine residue 106 of DJ-1. Overexpression of DJ-1 did not rescue the mitophagy defect of PINK1- or parkin-deficient cells. These findings position DJ-1 downstream of PINK1 and parkin in the same pathway and suggest that disruption of PINK1/parkin/DJ-1-mediated mitophagy is a common pathogenic mechanism in autosomal recessive Parkinson's disease.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Proteínas Quinases / Mitofagia Limite: Humans Idioma: En Revista: Brain Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Proteínas Quinases / Mitofagia Limite: Humans Idioma: En Revista: Brain Ano de publicação: 2022 Tipo de documento: Article