Parkinson disease (PD) is the second most common neurodegenerative disease. The hallmark pathology of PD is progressive degeneration of nigrostriatal dopamine (NSDA) neurons, but the hypothalamic tuberoinfundibular (TI) DA neurons remain intact. A similar pattern of susceptibility can be seen in these DA neuronal populations following single acute exposure to the mitochondrial Complex I inhibitor, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this dissertation, mitochondrial structure and function in NSDA and TIDA axon terminals in WT mice were investigated. An increase in mitochondrial bioenergetics, mass, and mitophagosomes were observed in mitochondria derived from medial basal hypothalamus (MBH) containing TIDA neurons as compared to striatum (ST) containing NSDA neurons. The ultrastructure of the mitochondria from the two brain regions did not differ, but MBH had higher numbers of mitochondria per synaptosome than ST. Mitochondrial function differed depending on the brain regions in WT mice. However, mitochondria derived from ST and MBH responded to Complex I inhibition in a similar manner. This suggests that intrinsic differences in the sensitivity of mitochondrial electron transport chain (ETC) enzymes to neurotoxicant inhibition are not responsible for differential susceptibility of NSDA and TIDA neurons to MPTP.Parkin is a 52Kda cytosolic protein originally identified by linkage analysis in autosomal recessive early onset PD. Parkin is reported to mediate mitochondrial quality control through autophagy of mitochondria, and increased parkin expression is associated with resistance of TIDA neurons to acute MPTP exposure. Parkin may protect against DA neurodegeneration by maintaining mitochondrial homeostasis in central DA neurons. To test this hypothesis, mitochondrial structure and function in NSDA and TIDA neurons were investigated in parkin null mice. Reduced mitochondrial maximal and spare respirations, mitochondrial mass, number of mitochondria per synaptosome, and disrupted mitochondrial ultrastructure were all observed in the absence of parkin. These results suggest that impaired mitochondrial function is due to decreased numbers of high quality mitochondria in DA axon terminals in the ST of parkin deficient mice. This may be due to loss of parkin-mediated mitochondrial quality control in NSDA neurons. Parkin rescue via rAAV expression in the midbrain failed to alter impaired mitochondrial function in parkin null mice. However, parkin overexpression prevented inhibition of maximum and spare respiration by MPTP. These results suggest parkin overexpression maintained functional mitochondria likely through autophagy in response to acute neurotoxicant exposure. Therefore, loss of parkin mediated mitochondrial quality control may contribute to loss of NSDA neurons in a neurotoxicant model of DA neuronal degeneration in PD.
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