MITOCHONDRIAL NADH DEHYDROGENASE AND CYP2D6 GENOTYPES IN LEWY-BODY PARKINSONISM

The cause of nerve-cell death in sporadic Parkinson's disease remains unknown, Although environmental factors have been traditionally implic ated in the etiology of Parkinson's disease, recent studies strongly s uggest that there is a genetic contribution to this multifactorial dis order, We studied archival brain tissue from clinically and neuropatho logically verified cases of Parkinson's disease, using nonradioactive cycle sequencing and restriction enzymatic analysis of polymerase chai n reaction products, Twenty-one Parkinsonian brains with brain stem Le wy-bodies and 77 control brains were genotyped at two mitochondrial lo ci previously implicated in the etiology of neurodegenerative disease. In addition, genotyping was performed for two alleles of the debrisoq uine 4-hydroxylase gene (CYP2D6), A heteroplasmic mtDNA(G5460A) missen se mutation in the ND2 subunit gene of NADH dehydrogenase was three ti mes more frequent in Parkinson cases (4/21) compared to controls (5/77 ), A homoplasmic mtDNA(A4336G) transition which alters the mitochondri al tRNA(Gln) gene product was found in one Parkinson case, Frequencies of the CYP2D6(G1934A) and CYP2D6(C2938T) alleles were not significant ly different between Parkinson cases and controls, Two Parkinsonian br ains with high degrees of heteroplasmy for the ND2(G5460A) mutation an d one CYP2D6(C2938T) homozygous case showed very high numbers of Lewy- bodies in the substantia nigra, The results of this study are in line with the concept that different genetic loci may be involved in Parkin son's disease susceptibility, They provide a hint that the ND2(5460) m utation, in combination with other factors, could play a role in disea se pathogenesis in a subset of patients. (C) 1996 Wiley-Liss, Inc.