Mutations of the gene encoding the catalytic subunit of polymerase gamma (POLG), the protein maintaining the mitochondrial genome, cause severe degeneration of the substantia nigra, a part of the brain involved in movement control and coordination. Degeneration of the substantia nigra is a central feature of Parkinson’s disease and is believed to cause most of the disorder’s motor complications. Surprisingly, patients with POLG mutations showed NO clinical signs of parkinsonism despite the fact that the neuronal fall out in their substantia nigra was more pronounced than that seen in patients with Parkinson’s disease.

In the first study (https://www.ncbi.nlm.nih.gov/pubmed/23625061 ) showed that dopaminergic neurones of the substantia nigra (the cells that are lost in Parkinson’s disease) are highly vulnerable to mitochondrial dysfunction and particularly mitochondrial DNA damage (Figure 1).

Furthermore, the lack of Parkinson-like features in our patients suggests that the motor complications that have been traditionally associated with degeneration of the substantia nigra are somehow counteracted and compensated for. We hypothesise that the additional thalamic and cerebellar dysfunction in our patients may play a role in counteracting the effects of nigral depletion. Further elucidation of the mechanisms involved is essential to our understanding of the pathophysiology of Parkinson’s disease and may help identify novel therapeutic targets

In a follow up study published in 2016 (https://www.ncbi.nlm.nih.gov/pubmed/26979109), we showed that the loss of substantia nigra neurones is associated with defects of mtDNA homeostasis. We found that it only occurred in diseases that were associated with defects in POLG and TWNK genes but not in diseases associated with primary mutations of mtDNA such as the MERRF and MELAS point mutations or single mtDNA deletions. This study strongly supports the hypothesis that accumulating somatic mtDNA damage plays an important role in this type of neurodegeneration.