Pingyue Pan, MD, PhD

The primary research interest in my lab is to understand the function and the regulation of dopaminergic neurons, with a particular focus on the synapse and the mechanisms of its dysregulation in disease conditions.  Dopaminergic signaling modulates a multitude of human behaviors including body movements, reward and addiction, as well as motivational behaviors. Loss of dopamine neurons in the Substantia Nigra leads to Parkinson’s disease (PD), yet questions remain as to why dopamine neurons are more vulnerable. We aim to understand dopamine neurons by analyzing known genetic PD risk factors and their signaling pathways both in vitro and in vivo at different parts of the brain.

Currently, we are investigating the role of the Synj1 gene in deregulating the basal ganglia function using mouse models. SYNJ1, also known as PARK20, is one of the synaptic genes associated with Parkinsonism. Synj1 polymorphism has also been found in autism, schizophrenia, and bipolar disorders, indicating the role of Synj1 in regulating the dopaminergic pathway. Indeed, both human and mouse studies suggests that partial loss of Synj1 function (either via disease-linked missense mutation or heterozygous deletion) leads to abnormal motor functions and an impaired dopaminergic pathway. The mechanism underlying dopaminergic dystrophy due to Synj1 deficiency is not well understood.

We use transgenic mouse models, primary dopamine neuron culture, quantitative imaging, as well as biochemical, behavioral, and pathological analyses to understand cell type, brain region-specific signatures, and vulnerabilities relevant to dopaminergic dysregulation. Additionally, we are interested in exploring the relationship between dopamine vulnerability and dopamine-dependent addiction mechanisms. Anatomically, the dorsostriatal dopamine pathway regulates motor function and the mesolimbic (medioventral) pathway is involved in addiction.

However, substantial crosstalk has been reported for the two dopaminergic pathways. For example, the dorsal striatum is also involved in goal-directed drug-seeking behavior; and epidemiological studies show that nicotine intake via tobacco smoking significantly reduces the risk of PD. We hope to use the Synj1 mouse as a handle to address the interesting crosstalk in dopamine signaling.  An important strength of the lab is the use of quantitative live cell imaging to understand cellular and synaptic functions. We have two imaging rigs (Nikon Ti2 with Andor Ultra 897 EMCCD camera and Nikon CREST spinning disk confocal microscope) for high-quality research.

Current Funding

1. NINDS R01 “The role of Synaptojanin1 in regulating the basal ganglia function”
2. NINDS R01-Supplement “The role of Synaptojanin1 in regulating the DAT trafficking”
3. Brain Health Institute Pilot grant “Genetic predisposition to cocaine tolerance”
4. RWJMS-startup fund 

Selected Publications

• Pan, P.Y.*, Sheehan, P., Wang, Q., Zhang, Y., Zhu, X., Wang, J., Li, X., Choi, I., Li, X., Saenz, J., Zhu, J., El Gaamouch, F., Zhu, L., Cai, D., and Yue, Z*. SYNJ1 Haploinsufficiency Causes Dopamine Neuron Vulnerability and α-synuclein Accumulation in Mice. Human Molecular Genetics 2020, *co-correspondence.
• Wang, Q., Zhang, Y., Wang, M., Song, W.M., Shen, Q., McKenzie, A., Choi, I., Zhou, X., Pan, P.Y., Yue, Z., Zhang, B. The landscape of multiscale transcriptomic networks and key regulators in Parkinson’s disease. Nature Communication 2019, 10(1):5234.
• Pan, P.Y., Zhu, Y., Shen, Y., and Yue, Z. Crosstalk between presynaptic trafficking and autophagy in Parkinson’s disease. Neurobiology of Disease 2018, pii: S0969-9961(18)301360
• Pan, P.Y., Li, X., Wang, J., Powell, J., Wang, Q., Zhang, Y., Chen, Z., Wicinski, B., Hof, P., Ryan, T.A. and Yue, Z. Parkinson’s disease associated LRRK2 hyperactive kinase mutant disrupts synaptic vesicle trafficking in ventral midbrain neurons. Journal of Neuroscience 2017, 37(47): 11366-11376.
• Pan, P.Y., Marrs, J., and Ryan, T.A. Vesicular glutamate transporter 1 orchestrates recruitment of other synaptic cargo proteins during synaptic vesicle recycling. Journal of Biological Chemistry 2015, 290(37): 22593-601.
• Pan, P.Y. and Ryan, T.A. Calbindin controls release probability in ventral tegmental area dopamine neurons. Nature Neuroscience 2012, 15(6): 813-5
• Pan, P.Y., Tian, J.H. and Sheng, Z.H. Snapin facilitates the synchronization of synaptic vesicle fusion. Neuron 2009, 61(3): 412-24.
• Kang, J.S., Tian, J.H.*, Pan, P.Y.*, Zald, P., Li, C., Deng, C., and Sheng, Z.H. Docking of Axonal Mitochondria by Synataphilin Controls Their Mobility and Contributes to Short-term Facilitation. Cell 2008, 132(1):137-48. (*equal contribution)