Human Molecular Genetics Advance Access originally published online on September 2, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 21 2807-2816
DOI: 10.1093/hmg/ddg304
© 2003 Oxford University Press
The DJ-1L166P mutant protein associated with early onset Parkinson's disease is unstable and forms higher-order protein complexes
1Department of Human Genetics, Section of Medical Genomics, VU University Medical Center, 1081 BT Amsterdam, The Netherlands, 2Department of Clinical Genetics, ErasmusMC, 3000 DR Rotterdam, The Netherlands, 3Neurogenetics Unit, IRCCS Neuromed, 86077, Pozzilli, Italy and 4Department of Neurological Sciences, La Sapienza University, 00185 Rome, Italy
Received June 29, 2003; Accepted August 27, 2003
Parkinson's disease (PD) is a common neurodegenerative disorder that involves the selective degeneration of midbrain dopaminergic neurons. Recently DJ-1 mutations have been linked to autosomal-recessive early-onset Parkinsonism in two European families. By using gel filtration assays under physiological conditions we demonstrate that DJ-1 protein forms a dimeric structure. Conversely, the DJ-1L166P mutant protein shows a different elution profile as compared with DJ-1WT both in overexpression cellular systems or in lymphoblasts cells, suggesting that it might form higher order protein structures. Furthermore we observed that the level of DJ-1L166P mutant protein in the patient's lymphoblasts was very low as compared with the wild-type protein. We excluded a potential transcriptional impairment by performing quantitative RT–PCR on the patient's material. Pulse-chase experiments in transfected COS-1 cells and cycloheximide treatment in control and patient lymphoblasts indicated that the mutant protein was rapidly degraded. This rapid turnover and the structural changes of DJ-1L166P mutant protein might be crucial in the disease pathogenesis.
* To whom correspondence should be addressed at: Department of Human Genetics, Section Medical Genomics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. Tel: +31 204449962; Fax: +31 204448285; Email: heutink{at}cncr.vu.nl
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