Mutations in two Parkinsonism-linked endocytic genes SYNJ1 and DNAJC6 have synergistic effects on dopaminergic axonal pathology
Xin Yi Ng1, Yumei Wu2*, Youneng Lin1*, Sidra Mohamed Yaqoob1*, Lois E Greene3, Pietro De Camilli2 and Mian Cao1,4
1Programme in Neuroscience and Behavioural Disorders, Duke-NUS Medical School, Singapore
2Departments of Neuroscience and Cell Biology, Howard Hughes Medical Institute, Program in Cellular Neuroscience, Neurodegeneration and Repair, Kavli Institute for Neuroscience, Yale University School of Medicine, USA. Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD.
3Laboratory of Cell Biology, NHLBI, National Institutes of Health, MD, USA
4Department of Physiology, National University of Singapore, Singapore
*These authors contributed equally
Parkinson’s disease (PD) is a neurodegenerative disorder characterised by defective dopaminergic (DAergic) input to the striatum. Mutations in two genes encoding synaptically-enriched clathrin-uncoating factors, synaptojanin 1 (SJ1) and auxilin, have been implicated in atypical Parkinsonism. SJ1 knock-in (SJ1-KIRQ) mice carrying a disease-linked mutation display neurological manifestations reminiscent of Parkinsonism. Here Dr Cao’s group reports that auxilin knockout (Aux-KO) mice display dystrophic changes of a subset of nigrostriatal DAergic terminals similar to those of SJ1-KIRQ mice. Furthermore, Aux-KO/SJ1-KIRQ double mutant mice have shorter lifespan and more severe synaptic defects than single mutant mice. These include increase in dystrophic striatal nerve terminals positive for DAergic markers and for the PD risk protein SV2C, as well as adaptive changes in striatal interneurons. The synergistic effect of the two mutations demonstrates a special lability of DAergic neurons to defects in clathrin uncoating, with implications for PD pathogenesis in at least some forms of this condition.