LAUSR

Mitochondrial dysfunction is recognized as being an important mechanism through which Parkinson’s disease (PD) can arise. In particular, decrease of mitochondrial complex 1 (MCI) activity in dopaminergic neurons of the substantia nigra (SN) has been observed in PD; however, its role in the pathogenesis of PD remains unclear. Mitochondrial protection or rescue therapies are potential approaches through which disease modification of PD may be achieved in the future. A recent publication by Gonzales-Rodríguez and colleagues assessed the metabolic, epigenetic, and clinical effects of disruption of MCI using a mouse model. Using “intersectional genomics,” the investigators “knocked out” the Ndufs2 gene from dopaminergic neurons in the mouse. The Ndufs2 gene encodes an essential subunit of the MCI catalytic core. A key finding was that the loss of MCI function in SN dopaminergic neurons was sufficient to induce progressive, levodopa-responsive parkinsonism in the mouse. A change in the metabolic profile of dopaminergic neurons was demonstrated, from the net ATPproducing phenotype to an ATP-consuming phenotype. Along with modest structural changes in mitochondria, isolated neurons showed metabolic reprogramming characterized by upregulation of glycolysis-related genes, together with downregulation of genes associated with oxidative phosphorylation and glycolysis inhibition. The loss of Ndufs2 in dopaminergic neurons also induced changes in the expression of genes involved in axonal growth and transport, synaptic transmission, and dopamine metabolism. Alongside metabolic and epigenetic changes, the investigators demonstrated a late emergence of gross motor deficits together with changes in SN dopaminergic release. Although animal models do not fully recapitulate human disease, the observations from experiments presented in this paper are nonetheless very informative. The investigators demonstrated, in an animal model, that severe disruption of nigral dopaminergic neuronal MCI function is sufficient to trigger progressive, axonal loss of function and levodopa-responsive parkinsonism. The gradual shift of phenotype from ATP producing to ATP consuming neurons, changes in dopamine release and pacemaker activity, are indicative of the plasticity of neuronal circuitry and highlight potential opportunities to promote resilience and rescue. The high correlation between dopaminergic depletion in the SN and the evolution of motor impairment suggest that both striatal and SN dopaminergic are necessary to trigger PD motor symptoms. Overall, the findings warrant further replication, to confirm the importance of nigral dopaminergic depletion as determinant of motor disability and further explain the loss of dopaminergic markers in the somatodendritic region of SN dopaminergic neurons. These findings may have important implications for the development of novel therapies for PD and other disorders, in which mitochondrial dysfunction plays a key role.