Cerebellar mitochondrial DNA deletion associated with survival of prolonged ischemia

Mitochondrial DNA (mtDNA) mutations are known to accumulate with age and ar e linked to several neurodegenerative disorders and diseases. We have inves tigated the accumulation of the mitochondrial 4977 bp deletion ("common del etion") in caudate nucleus and cerebellum in 25 individuals aged 3 month to 84 years. 100 ng total DNA extracted from each brain region was used for t he amplification of specific fragments of undeleted and deleted DNA in one PCR reaction. Fluorescence-labeled fragments were quantified using the auto mated Genetic Analyser 310. As expected the amount of the 4977 bp deletion increased in the caudate nucleus with advancing age. However the deletion w as barely detectable in cerebellar tissue, even in old individuals. Only in 6 of 25 cases the specific deletion could be demonstrated. Clinical evalua tion and microscopic examination of these 6 cases revealed findings of prol onged ischemia. Free radicals can induce oxidative damage especially of mit ochondrial DNA lending among others to the 4977 bp deletion. The high amoun t of the deletion in caudate nucleus could be a result of its concentration of monoaminooxidase of the deposits of free iron which both can generate a lot of free radicals. Cerebellar tissue is probably better protected by an tioxidant defense mechanisms, which have not been yet identified. We sugges t that the increase of the amount of the 4977 bl, deletion might he a sensi tive marker for prolonged cerebral and systemic ischemia and thus be of pat hophysiological and diagnostic importance.