DJ-1-mediated metabolic efficiency determined the vulnerability of midbrain dopaminergic neurons in Parkinson’s disease

Metabolic insufficiency has been identified as a key factor underpinning the degeneration of midbrain dopaminergic neurons during the course of Parkinson’s disease. Our studies suggest that a specific interaction of Parkinson’s protein, DJ-1 (Park7) with the mitochondrial F1Fo ATP synthase is required for stability of the mitochondrial inner membrane, which is required for neuronal and synaptic bioenergetic efficiency. To determine whether this molecular mechanism contributes to the vulnerability in Parkinson’s disease, we examined the interaction between the two molecules in different dopaminergic sub-populations of post-mortem Parkinson’s disease brains. We found that the level of DJ-1 and ATP synthase interaction was different between the mesolimbic and nigrostriatal dopaminergic pathways. We also observed a significant difference in interaction between Parkinson’s disease and age-matched control brains. Our studies suggest that this interaction plays a key role in determining the mitochondrial heterogeneity that contributes to the specific vulnerability of midbrain dopaminergic neurons. This study offers the first evidence in humans that the efficient coupling of oxidation to phosphorylation in mitochondria contributes directly to the survival of midbrain dopaminergic neurons and the degeneration observed in Parkinson's disease.