Mitochondrial ND5 mutations in idiopathic Parkinson’s disease

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Abstract

Idiopathic Parkinson’s disease (PD) is characterized by a systemic loss of activity of complex I (NADH:ubiquinone oxidoreductase), the target enzyme of the parkinsonism producing neurotoxin, MPTP. Cybrid experiments strongly suggest that the loss of complex I activity arises from mitochondrial DNA. We prospectively evaluated low frequency, amino acid changing, heteroplasmic mutations in a narrow region of ND5, a mitochondrial gene encoding a complex I subunit, in brain tissue from PD and controls. The presence or absence of amino acid changing mutations correctly classified 15 of 16 samples. Heteroplasmic mutations in a specific region of ND5 largely segregate PD from controls and may be of major pathogenic importance in idiopathic PD.

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Methods

Methods employed in this study were as previously described [9]. Genomic DNA was extracted from frontal lobe tissue from 8 idiopathic PD samples and 8 similarly aged controls (PD mean age, 78; control mean age, 74; ns). The region of interest in ND5 was PCR amplified and 96 independent clones from each sample were then cycle sequenced. Sequencer data were aligned against the wildtype sequence (Sequencher, Gene Codes) and all potential mutations were operator verified. Usable sequence data were

Results

Results of the present study are summarized and compared with the results of the previous study over this region (Table 1) [9]. Fifteen of 16 samples studied were correctly identified as either PD or control on the basis of the presence or absence of amino acid changing mutations in the specific regions studied. A single control was misidentified as PD. Whether or not this individual would have developed Parkinson’s disease later in life is unknowable. In several instances we identified

Discussion

Our initial broad-ranging and in-depth study of heteroplasmic mtDNA mutations in idiopathic PD suggested on retrospective analysis that a small region ND5 and to a lesser extent a small region in ND2 harbor mutations segregating PD from controls. The present prospective study appears to confirm that observation with respect to ND5. Both studies identified relevant heteroplasmic mutations but at frequencies well below that previously associated with disease causing mutations. The catalytic

Acknowledgments

This work was supported by the Dana Foundation and by a Morris K. Udall Parkinson’s Disease Center of Excellence grant from NINDS. We are grateful to Dr. Ted Dawson and colleagues, Dr. Ronald Hamilton, and Dr. Ali Rajput for tissue samples.

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