mtDNA damage in Parkinson's and aging

There is a nice short review by Giovanni Manfredi in the current Nature Genetics on mtDNA damage and Parkinson's. The paper is really a perspective accompanying two short research papers, but it is more comprehensible than the original research:

mtDNA mutations and mitochondrial dysfunction have long been implicated in aging, Parkinson disease and other age-related neurodegenerative diseases. However, despite extensive efforts and a body of supporting literature, conclusive evidence has not been produced. On pages 518 and 515 of this issue, Kraytsberg and colleagues and Bender and colleagues investigate the role of mtDNA mutations in the degeneration of dopaminergic neurons of the substantia nigra, which occurs in aging and Parkinson disease (Fig. 1). Their studies reveal accumulation of mtDNA deletions in aged dopaminergic neurons, providing evidence for the involvement of mtDNA damage in the demise of these cells.

The key is that these particular neurons accumulate mtDNA damage at an especially high rate, so that you have to isolate them to find the significant effect.

This part is very interesting:

As a whole, the substantia nigra contained many different types of mtDNA deletions, but each neuron contained only a single type, indicating that mtDNA deletions are acquired throughout life. These findings also imply that the mtDNA of substantia nigra neurons is turned over at a sufficient rate to allow a single deleted mtDNA molecule to multiply itself at the expense of normal mtDNA.

It is a complete mystery why these particular neurons should have such a rapid accumulation of damaged mtDNA, and puzzling because it would require an intracellular mechanism for the replacement of normal by mutant mtDNA, such as differential reproduction of mutant mtDNA within cells (as the article points out).

References:

Manfredi M. 2006. mtDNA clock runs out for dopaminergic neurons. Nature Genet 38:507-508. DOI link