Human Molecular Genetics Advance Access published online on September 2, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg304
© 2003 by Oxford University Press
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1 Department of Human Genetics, section Medical Genomics, VU University Medical Center, 1081 BT Amsterdam; Department of Clinical Genetics, ErasmusMC, 3000 DR Rotterdam, The Netherlands
* To whom correspondence should be addressed. E-mail: heutink{at}cncr.vu.nl.
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 Parkinsoninsm 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 to DJ-1WT both in over-expression 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 patient's lymphoblasts is very low as compared to the wild type protein. We excluded a potential transcriptional impairment by performing quantitative RT-PCR on patient's material. Pulse-chase experiments in transfected COS-1 cells, and cycloheximide treatment in control and patient lymphoblasts indicated that the mutant protein is rapidly degraded. This rapid turnover and the structural changes of DJ-1L166P mutant protein might be crucial in the disease pathogenesis.
Article
The DJ-1L166P mutant protein associated with early onset Parkinson's disease is unstable and forms higher order protein complexes
2 Neurogenetics Unit, IRCCS Neuromed, 86077, Pozzilli, Italy
3 Department of Clinical Genetics, ErasmusMC, 3000 DR Rotterdam, The Netherlands; Department of Neurological Sciences, La Sapienza University, 00185 Rome, Italy
4 Department of Clinical Genetics, ErasmusMC, 3000 DR Rotterdam, The Netherlands
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