SYNGR3 is a synaptic vesicle membrane protein that functions as a critical regulator of dopaminergic neurotransmission 1. Primary Function: SYNGR3 facilitates dopamine uptake by directly interacting with the dopamine transporter (DAT) at striatal presynaptic terminals, enhancing dopamine reuptake from the synaptic cleft 2. This interaction is spatially co-localized and confirmed by co-immunoprecipitation and transmission electron microscopy 2. Mechanism: SYNGR3 is regulated transcriptionally by NURR1 through non-canonical NGFI-B response elements, with C-DIM12 activation increasing SYNGR3 expression in neuronal cells 1. Disease Relevance: Reduced SYNGR3 expression is observed in Parkinson's disease (PD) brains 2. However, recent evidence reveals complex roles: SYNGR3 overexpression improves dopamine uptake and behavioral outcomes in LRRK2 mutant PD models 2, while paradoxically, elevated SYNGR3 accelerates α-synuclein aggregation and neurodegeneration in A53T transgenic PD models 3. SYNGR3 is also implicated in cocaine use disorder, where low expression correlates with addiction vulnerability, and overexpression reduces drug-seeking behavior 4. Clinical Significance: SYNGR3 serves as a diagnostic biomarker for PD alongside SLC18A2 and CALB1 5, and as a prognostic marker in HPV-positive head and neck cancers 6.