Mian CAO

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-KI^RQ) 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-KI^RQ 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.