NeuralCipher Research overview
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RAB12 is a small GTPase and a validated substrate of LRRK2, a kinase genetically linked to Parkinson's disease (PD). While RAB12-LRRK2 signaling has been implicated in ciliogenesis and immune regulation, the neuronal function of RAB12 remains largely unexplored. Here, we investigated the role of RAB12 in synaptic physiology using Rab12 knockout (KO) mice. Rab12 KO mice developed normally but exhibited increased locomotor activity in adulthood. Electrophysiological recordings from striatal slices revealed enhanced presynaptic release probability and increased excitatory drive onto medium spiny neurons. Consistently, live-cell imaging of cultured cortical neurons revealed that Rab12 deletion facilitated, while Rab12 overexpression inhibited, synaptic vesicle exocytosis. Biochemical fractionation showed enrichment of RAB12 in synaptic vesicle-associated fractions containing presynaptic components. Proteomic analysis of Rab12 KO striatal synaptosomes further identified alterations in proteins involved in synaptic membrane trafficking pathways. Together, these findings establish RAB12 as a negative regulator of synaptic vesicle exocytosis and excitatory neurotransmission in vivo. Our study defines a physiological role for RAB12 in synaptic function and provides a basis for future investigation into how LRRK2-dependent RAB12 signaling may contribute to neuronal dysfunction in PD.
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