Theses Doctoral

Selective vulnerability of dopaminergic neurons in a novel model of Parkinson's disease

Griffey, Christopher Joseph

Parkinson’s disease (PD) is characterized by the degeneration of midbrain dopaminergic neurons. Genetic studies have revealed causative and risk loci associated with a proportion of PD cases, such as PRKN/PARK2, encoding parkin and when mutated causes a rare familial form of autosomal recessive PD. Cell-based studies have linked parkin to mitochondrial turnover by autophagy, but to date, manipulating this gene in rodents has not robustly recapitulated core features of PD.

Reconciling these results is essential to determine parkin’s role in mitochondrial biology, brain physiology, and PD pathogenesis. Here, we find that global, inducible deletion of Prkn/Park2 (parkin iKO) in the adult mouse leads to age-dependent motor impairments that are responsive to levodopa treatment. We report that these behavioral defects are associated with progressive pathology in dopaminergic neurons, regional gliosis and lipid oxidation changes, culminating in the selective degeneration of nigrostriatal dopaminergic neurons.

We also present a new, in vivo mitophagy reporter system to investigate the relationship of parkin’s described roles in mitochondrial homeostasis to the observed phenotypes. These results give critical insight into parkin’s contribution to dopaminergic neuron stability in the mammalian brain, and provide two distinct and novel organismal tools to investigate mitochondrial homeostasis and PD pathogenesis.


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More About This Work

Academic Units
Neurobiology and Behavior
Thesis Advisors
Yamamoto, Ai
Ph.D., Columbia University
Published Here
February 28, 2024