Abstract for presentation at 11th International Congress of Human Genetics

Association of PINK1 and DJ-1 Confers Digenic Inheritance of Early Onset Parkinson’s Disease

  • Dr Beisha Tang, Xiangya Hospital, Central South University, China
  • Dr Hui Xiong, Burnham Institute for Medical Research, United States
  • Dr Ping Sun, Burnham Institute for Medical Research, United States
  • Dr Yuhu Zhang, Xiangya Hospital, Central South University, China
  • Dr Qian Pan, National Laboratory of Medical Genetics, Xiangya Hospital, Central South University, China
  • Dr Jiahui Xia, National Laboratory of Medical Genetics, Xiangya Hospital, Central South University, China
  • Dr Kun Xia, National Laboratory of Medical Genetics, Xiangya Hospital, Central South University, China
  • Zhuohua Zhang, Burnham Institute for Medical Research, United States

    • Parkinson’s disease (PD) is the most frequent neurodegenerative movement disorder characterized by age-dependent resting tremor, muscular rigidity, and akinesia. Majority of the PD cases appear to be sporadic. However, specific genetic defects are linked to familial form of PD that resemble idiopathic PD. Mutations in at least 6 genes are individually linked to familial form of PD, including autosomal dominant mutations in ?-synuclein, uchL1 and LRRK2 and autosomal recessive mutations in parkin, PINK1 and DJ-1. Among the three recessive PD linked genes, both homozygous and heterozygous mutations of these genes are found to associate with PD cases. The mechanism for PD caused by these heterozygous mutations is not known. We here report identification of a family with PD patients harboring 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 rescues 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.

    Conference Organiser - ICMS Pty Ltd