Symposium 1

Asst. Prof Cao Mian

Assistant Professor

Neuroscience and Behavioural Disorders Programme

Duke-NUS Medical School

Dr Cao is an Assistant Professor in the Neuroscience and Behavioural Disorders programme at Duke-NUS Medical School since 2019. His research focuses on the functional relationship of several Parkinson's disease genes with the endocytic traffic of synaptic vesicles. He earned his PhD in Biochemistry from the Hong Kong University of Science and Technology in 2009, and subsequently joined Dr Pietro De Camilli's laboratory at Yale University/Howard Hughes Medical Institute as a Postdoctoral Associate in the Department of Cell Biology. He was then promoted to Associate Research Scientist in the Department of Neuroscience at Yale University in 2015.

Session:

Building from the Bench (Model Systems to Understand Disease Mechanisms)
12 April 2024, 1045 - 1215, NAK Auditorium

Presenting Title:

Impaired Synaptic Vesicle Recycling in Parkinson’s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by selective loss of dopamine neurons in the midbrain and defective dopamine input to the striatum. Mutations in two 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.

Here I will talk about several SJ1 and auxilin mutant mouse models we have generated and characterized. SJ1 knock-in (SJ1-KIRQ) mice carrying a disease-linked missense mutation and auxilin knockout (Aux-KO) mice phenocopy each other and display neurological manifestations reminiscent of Parkinsonism, including dystrophic changes of nigrostriatal dopamine terminals. Furthermore, Aux-KO/SJ1-KIRQ double mutant mice have shorter lifespan, more severe synaptic defects and dystrophic dopamine terminals than single mutant mice, as well as adaptive changes in striatal interneurons. In addition, selective and complete loss of SJ1 in dopamine neurons in SJ1 conditional KO (cKO) mice leads to similar dystrophic changes of dopamine terminals in a cell autonomous and gene dosage dependent manner.

In summary, the similar pathology and synergistic effect of SJ1 and auxilin mutations demonstrates a special lability of dopamine neurons to defects in clathrin uncoating, with implications for PD pathogenesis in at least some forms of this condition.

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