2nd Workshop Neurogenetics in Germany, Munich, October 19-21, 1995
Several studies indicate that mitochondrial DNA mutations play a role in the etiology of complex disorders such as Parkinson disease (PD) and Alzheimer disease (AD), as well as in normal aging. In the case of PD, a point mutation at nucleotide 5460 affecting the ND2 subunit of NADH dehydrogenase (EC 126.96.36.199; complex I of the respiratory chain) was found to be more common in PD brains compared with normal and AD controls (Kösel et al., submitted).
We have now studied the distribution of mutated and wild-type mtDNA in a large number of different anatomical regions in PD brains with very high and very low ratios of the different mtDNA species, respectively. DNA was extracted from formalin-fixed and paraffin-embedded archival brain tissue, amplified by PCR, and digested using the restriction enzyme Hph I. The proportion of mutated mtDNA was determined by quantitative laser densitometry.
Comparing up to 16 different tissue areas, we found varying degrees of mtDNA heteroplasmy in different brain regions. For instance, in one brain it appeared that hindbrain regions such as cerebellum and the nuclei of the cranial nerves carried significantly lower amounts (88%) of G5460A mutated DNA than the nuclei of the basal ganglia. Relative levels of mtDNA heteroplasmy were 96% and 94% in caudatum and putamen, respectively. Apart from their possible relevance for PD pathogenesis our results could provide new insights into brain development. Additional cases are currently being studied to determine the exact relationship between the degree of mtDNA heteroplasmy in specific neuronal populations and the histological as well as biochemical changes accompanying dopaminergic cell death in PD.
Supported by the Deutsche Forschungsgemeinschaft (Gerhard Hess-Programm).
Parkinson disease (PD)
G5460A mutant mtDNA