Journal Article

Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease

Beisha Tang, Hui Xiong, Ping Sun, Yuhu Zhang, Danling Wang, Zhengmao Hu, Zanhua Zhu, Hong Ma, Qian Pan, Jia-hui Xia, Kun Xia and Zhuohua Zhang

in Human Molecular Genetics

Volume 15, issue 11, pages 1816-1825
Published in print June 2006 | ISSN: 0964-6906
Published online April 2006 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddl104
Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease

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Mutations in genes encoding both DJ-1 and pten-induced kinase 1 (PINK1) are independently linked to autosomal recessive early-onset familial forms of Parkinson's disease (PD). We here report identification of a family with PD patients harboring novel heterozygous missense mutations in both PINK1 and DJ-1 genes encoding DJ-1A39S and PINK1P399L, respectively. In transfected cells, DJ-1 interacts with PINK1. PINK1P399L is less stable than the wild-type protein and is degraded via the ubiquitin-mediated proteasomal pathway. Expression of wild-type DJ-1 increased steady-state levels of PINK1, whereas expression of DJ-1A39S reduced steady-state levels of PINK1. Furthermore, co-expression of wild-type DJ-1 and PINK1 suppresses neurotoxin 1-methyl-4-phenylpyridinium (MPP+)-induced death of dopaminergic SH-SY5Y cells. In contrast, co-expression of PD-associated DJ-1A39S and PINK1P399L significantly potentiated susceptibility of SH-SY5Y cells to MPP+-induced cell death. This study reports the first case of autosomal recessive PD with digenic inheritance and demonstrates that DJ-1 and PINK1 physically associate and collaborate to protect cells against stress via complex formation.

Journal Article.  6442 words.  Illustrated.

Subjects: Genetics and Genomics

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