Project Summary Regulated synaptic transmission is essential in maintaining the proper function of the brain, and mutations in synaptic genes are often linked to neurological and neurodegenerative disorders. In the parent grant, we propose to uncover the molecular and cellular mechanisms of the synaptic gene, SYNJ1 (encoding synaptojanin1, synj1), in contributing to dysfunction of the basal ganglia for motor control. Missense mutations in SYNJ1 (known as PARK20) are associated with early-onset atypical Parkinsonism, featured by an impaired dopaminergic system. However, the mechanism whereby synj1 partial loss-of-function results in the dysfunction of the dopaminergic pathway in the basal ganglia remains unclear. We hypothesize that loss of SYNJ1 dysregulates important signaling lipids, which results in aberrant calcium channel function, impaired membrane trafficking and altered dopamine release. This supplement is developed specifically for Jacqueline (Jackie) Saenz, a graduate student with underrepresented ethnic background, for her PhD thesis work and career development. It is complimentary to the Aim 3 in the parent grant in investigating how SYNJ1 regulates dopamine signaling. Jackie will be focusing on analyzing the function and endocytic trafficking of the dopamine transporter (DAT) in relation to dopamine signaling. She will be using heterologous cells as well as neurons from our newly developed conditional SYNJ1 deletion mouse to determine that DAT endocytosis and activity are regulated by the enzymatic domains of synj1 and their downstream lipid signaling pathways. Completion of the study will help us further understand the role of synj1 in DA signaling and to expose Jackie to a wide range of cutting-edge research strategies for her future research development.