Human Molecular Genetics Advance Access published online on April 21, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl104
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1 National Laboratory of Medical Genetics and Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China
* To whom correspondence should be addressed. 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, while expression of DJ-1A39S reduced steady-state levels of PINK1. Furthermore, coexpression of wild-type DJ-1 and PINK1 suppresses neurotoxin 1-methyl-4-phenylpyridinium (MPP+)-induced death of dopaminergic SH-SY5Y cells. In contrast, coexpression 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.
Received February 20, 2006
Revised April 12, 2006
Accepted April 12, 2006
Article
Association of PINK1 and DJ-1 Confers Digenic Inheritance of Early Onset Parkinson's Disease
Beisha Tang 1,
Hui Xiong 2,
Ping Sun 2,
Yuhu Zhang 1,
Danling Wang 2,
Zhengmao Hu 1,
Zanhua Zhu 1,
Hong Ma 2,
Qian Pan 1,
Jia-hui Xia 1,
Kun Xia 1,
and
Zhuohua Zhang 2 *
2 Burnham Institute for Medical Research, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA
Zhuohua Zhang, E-mail: benzz{at}burnham.org
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