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Human Molecular Genetics Advance Access originally published online on April 21, 2006
Human Molecular Genetics 2006 15(11):1816-1825; doi:10.1093/hmg/ddl104
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Beisha Tang1,2, Hui Xiong3, Ping Sun3, Yuhu Zhang1,2, Danling Wang3, Zhengmao Hu1, Zanhua Zhu1, Hong Ma3, Qian Pan1, Jia-hui Xia1, Kun Xia1 and Zhuohua Zhang3,*

1National Laboratory of Medical Genetics and 2Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China and 3Burnham Institute for Medical Research, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA

* To whom correspondence should be addressed. Tel: +1 8587136286; Fax: +1 8587136273; Email: benzz{at}burnham.org

Received February 20, 2006; Accepted April 12, 2006

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.


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