Mus musculus strain:C57BL/6J Metagenome

A hallmark of idiopathic Parkinson disease (PD) is the loss of functional mitochondrial complex I (MCI), a critical element in the electron transport chain, in the substantia nigra (SN). Using either a germline deletion or an inducible deletion, we found that knocking out the catalytic subunit of MCI (Ndufs2) in SN dopaminergic neurons transforms their mitochondria into net consumers of adenosine triphosphate (rather than producers) and results in progressive, levodopa-responsive parkinsonism. In these so-called MCI-Park mice, as in humans, the DA neuron pathology begins in nigrostriatal axons and then progresses to the somatodendritic region. No other mouse model to our knowledge has this human-like sequencing of basal ganglia pathology. The unique, progressive staging in the pathology of these mice should provide clues about PD pathogenesis and the network pathophysiology driving symptoms. In so doing, they should provide an important testbed for new symptomatic and disease-modifying therapies.