Description:

Dr. Mian Cao Programme in Neuroscience and Behavioural Disorders, Duke-NUS Medical School, Singapore PhD.,

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, characterized by the selective loss of dopamine (DA) neurons in the midbrain and defective DA input to the striatum. Mutations in the genes encoding synaptically-enriched clathrin-uncoating factors, synaptojanin 1 (SJ1) and auxilin, which are involved in synaptic vesicle recycling, have been implicated in atypical Parkinsonism. Our previous studies revealed that SJ1 knock-in (SJ1-KIRQ) mice harboring a disease-linked missense mutation and auxilin knockout (Aux-KO) mice phenocopy each other, exhibiting neurological features akin to Parkinsonism, including dystrophic nigrostriatal DA terminals. Double mutants (Aux-KO/SJ1-KIRQ) show exacerbated synaptic defects and DA terminal dystrophy compared to single mutants. Recently, we developed dopamine neuron-specific SJ1 conditional knockout (SJ1-cKODA) mice, which display severe, widespread dystrophy of striatal DA terminals and impaired DA metabolism/release, underscoring a cell-autonomous role for SJ1 in midbrain DA neurons. Notably, despite marked DA deficiency, SJ1-cKODA mice do not exhibit obvious motor coordination deficits but show a pronounced induction of striatal tyrosine hydroxylase-positive interneurons (THINs). These THINs express multiple DA markers and form connections with degenerating DA terminals, suggesting a local compensatory mechanism. Overall, the gene dosage-dependent pathology and synergistic effects of SJ1 and auxilin mutations highlight the unique vulnerability of DA neurons to defects in clathrin-mediated synaptic vesicle recycling, emphasizing its critical role in early PD pathogenesis.