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Parkinson's disease (PD) is the second most common neurodegenerative disorder. Genetic studies have recently identified several PD-linked proteins that are involved in endocytic trafficking at the synapse, suggesting impaired synaptic transmission is an early feature of PD. The long-term goal of my laboratory is to elucidate the pathogenic mechanisms of PD and reveal new potential therapeutic targets for the treatment of PD. Specifically, we will investigate how the impaired synaptic membrane trafficking results in selective neurodegeneration of dopaminergic neurons in PD. We will also study the potential synergistic function of several PD-linked proteins on synaptic endocytic pathway. Previously, we have identified a novel PD mutation in Synaptojanin1/PARK20, and developed a Knock-In mouse model which recapitulates human patients’ manifestations. We plan to perform biochemical, cell biological, genetic, physiological, pathological and behavioral experiments to address these questions using the PD mouse models and iPSC-derived human patient neurons.

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1. Jin W, Ge WP, Xu J, Cao M, Peng L, Yung W, Liao D, Duan S, Zhang M, Xia J. Lipid binding regulates synaptic targeting of PICK1, AMPA receptor trafficking, and synaptic plasticity. J Neurosci. 2006 Mar 1; 26(9): 2380-90.
2. Cao M, Xu J, Shen C, Kam C, Huganir RL, Xia J. PICK1-ICA69 Heteromeric BAR Domain Complex Regulates Synaptic Targeting and Surface Expression of AMPA Receptors. J Neurosci. 2007 Nov 21; 27(47): 12945-56.
3. Cao M*, Mao Z*, Kam C, Xiao N, Cao XX, Shen C, Cheng KY, Xu AM, Lee KM, Jiang LW, Xia J. PICK1 and ICA69 Control Insulin Granule Trafficking and Their Deficiencies Lead to Impaired Glucose Tolerance. * These authors contributed equally to this work. PLOS Biology 2013;11(4):e1001541.
4. Krebs CE, Karkheiran S, Powell JC, Cao M, Makarov V, Darvish H, Di Paolo G, Walker RH, Shahidi GA, Buxbaum JD, De Camilli P, Yue Z, Paisán-Ruiz C. The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive parkinsonism with generalized seizures. Hum Mutat. 2013 Sep;34(9):1200-7.
5. Cao M, Milosevic I, Giovedi S, De Camilli P. Up-regulation of Parkin in endophilin mutant mice. J Neurosci. 2014 Dec 3; 34(49): 16544-9.
6. Hardies K, Cai Y, Jardel C, Jansen AC, Cao M, May P, Djémié T, Hachon Le Camus C, Keymolen K, Deconinck T, Bhambhani V, Long C, Sajan SA, Helbig KL; AR working group of the EuroEPINOMICS RES Consortium., Suls A, Balling R, Helbig I, De Jonghe P, Depienne C, De Camilli P, Weckhuysen S. Loss of SYNJ1 dual phosphatase activity leads to early onset refractory seizures and progressive neurological decline. Brain. 2016 Sep; 139(Pt 9):2420-30.
7. Cao M, Wu YM, McCartney A, Ashrafi G, Wheeler H, Bushong EA, Boassa D, Ellisman MH, Ryan TA and De Camilli P. Parkinsonism mutation in Synaptojanin 1 leads to impaired synaptic vesicle recycling and synaptic degeneration in dopaminergic neurons. Neuron 2017 Feb 22;93(4):882-896. (F1000 Prime recommended)
8. Cao M, Park DH, Wu YM and De Camilli P. Absence of Sac2/INPP5F enhances the phenotype of a Parkinson’s disease mutation of synaptojanin 1. PNAS 2020 Jun 2;117(22):12428-12434
9. Yang SS, Park DH, Manning L, Hill S, Cao M, Xuan Z, Gonzalez I,  Shao L, Okeke I,  De Camilli P,  Colón-Ramos. DA Presynaptic autophagy is coupled to the synaptic vesicle cycle via ATG-9. Neuron 2022 Jan 20;S0896-6273(21)01076-X
10. The interaction between E3 ubiquitin ligase Parkin and mitophagy receptor PHB2 links inner mitochondrial membrane ubiquitination to efficient mitophagy. Sun S, Hou H, Ma G, Ma Q, Li N, Zhang L, Dong C, Cao M, Tam KY, Ying Z, Wang H. J Biol Chem. 2022 Dec;298(12):102704.
11. Ng XY, Wu YM, Lin Y, Yaqoob SM, Greene LE, De Camilli P, Cao M. Mutations in Parkinsonism-linked endocytic proteins synaptojanin1 and auxilin have synergistic effects on dopaminergic axonal pathology. NPJ-Parkinson’s disease 2023 Feb 15;9(1):26.