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ACCEPTED MANUSCRIPT mtDNA deletions, implying that they originated from clonal expansion. High levels (> 60%) of mtDNA deletions were found in neurons deficient for cytochrome c oxidase (COX, complex IV), three catalytic subunits of which are encoded by mt DNA. These observations suggest that the increase in mtDNA deletions above a critical threshold might be causally related to respiratory chain deficiency. Bender et al. reported that levels of mtDNA deletions were slightly higher in dopaminergic neurons from PD patients in comparison to age-matched controls. Accumulation of mtDNA deletions was not observed in hippocampal neurons, pyramidal neurons of the cerbral cortex or cerebellar Purkinje cells of aged individuals, indicating a highly specific process. Interestingly, there seems to be no differences in the nature of aging- or disease-related mtDNA deletions detected in single substantia nigra neurons [95]. It will now be important to addresss the question why dopaminergic neurons of the substantia nigra are particularly vulnerable to mtDNA detetions. Both, the high oxidative burden within these cells and defective mtDNA replication could contribute to this selective vulnerability. In this context it may be interesting to note that patients with mutations in the gene encoding mitochondrial DNA polymerase (POLG) accumulate multiple mtDNA mutations and develop parkinsonism [96]. In addition, ACCEPTED MANUSCRIPT variants in the POLG CAG-repeat region, encoding a polyglutamine tract, seem to be a predisposing factor in sporadic PD [97]. A link between mtDNA and neurodegeneration has further been substantiated by genetic mouse models. A conditional knockout of TFAM in midbrain dopaminergic neurons caused reduced mtDNA expression and respiratory chain deficiency and neuronal cell death, leading to progressive, L-dopa-responsive impairment of motor functions [98]. There are several reports linking PD to specific mtDNA haplogroups or 13
ACCEPTED MANUSCRIPT mtDNA point mutations, but not all of them could be confirmed in other studies (rev. in [6, 86]). Clearly, maternally inherited mtDNA mutations seem to be rarely associated with PD. By using the cybrid technique it has been observed that mtDNA from PD patients induces a complex I defect in healthy recipient cells, leading to the conclusion that complex I deficiency at least in some PD patients might be a systemic phenomenon [99-101]. To generate cybrid (which stands for cytoplasmic hybrid) cells, human SH-SY5Y cells are depleted of mtDNA by long-term exposure to ethidium bromide. The resulting cells are then fused with platelets from PD patients or controls to re-introduce mtDNA. This approach has been challenged by another group using cybrid cells, reporting that alterations in respiratory chain activity do not correlate with PD mtDNA [102]. So far, there is no clear evidence that mtDNA mutations are the primary culprit for PD. MtDNA mutations rather occur in the context of increasing cellular stress and decreasing fidelity of cellular stress defence systems. Notwithstanding, clonal expansion of these mutations can functionally impair the respiratory capacity and thus, precipitate degeneration of vulnerable neuronal populations. ACCEPTED MANUSCRIPT 2. Familial PD and mitochondria Since 1997 when α-synuclein was described as the first gene associated with familial PD, four other genes have conclusively been linked to autosomal recessive (parkin, PINK1, DJ-1) or dominant (LRRK2) parkinsonism (Tab. 1; for reviews on PD genetics see [3, 103-106]). Mutations in ATP13A2, encoding a P-type lysosomal ATPase, were identified in two kindreds with Kufor-Rakeb syndrome, a multisystemic neurodegenerative disorder which in addition to juvenile/early-onset parkinsonism shows pyramidal tract dysfunction and cognitive impairment [107]. 14
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