LRRK2 mediated cellular and synaptic events in the striatum Chuyu Chen1, Harry Xenias 2, Chrissy Makariou-Pikis1, Bharanidharan Shanmugasundaram1, Guoxiang Liu1, Savio Chan 2, Loukia Parisiadou2 1Department of Pharmacology, 2Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Il, USA Mutations in LRRK2 gene represent a strong genetic risk for both hereditary and sporadic forms of Parkinson's disease (PD). Despite the importance of LRRK2 in PD, there are still several fundamental aspects of LRRK2 function that remain unresolved at this time. LRRK2 is significantly enriched in spiny projection neurons (SPN) in the dorsal striatum. This cellular expression pattern argues that LRRK2 mutations contribute to striatal pathophysiology in PD. The function of LRRK2 in the striatum has remained relatively under-investigated; however, we recently showed that LRRK2 directs PKA signaling in SPNs. The LRRK2R1441C pathogenic mutation that impairs the binding of PKA with LRRK2 leads to increased levels of PKA in the dendritic spines that, in turn, result in aberrant synaptic PKA signaling. The components of PKA enzyme in neurons are confined to sub-cellular compartments, ensuring a spatial and temporal regulation of PKA signaling. Our data suggest that LRRK2 is strategically located in the dendritic shaft to organize signaling events in a spatiotemporal way. Thus, we propose that increased synaptic PKA activity in LRRK2R1441C SPNs stems from altered subcellular compartmentalization of PKA. As PKA is a critical effector of dopamine receptors, we provide evidence that LRRK2R1441C mutation impacts dopaminergic signaling in SPNs. Specifically, SPNs harboring LRRK2R1441C mutation show an abnormal elevation in PKA activity in response to dopamine receptor Drd1 activation. In addition, LRRK2R1441C SPNs show increased sensitivity to dopamine depletion as well as altered behavioral responses, suggesting a novel role of LRRK2 in dopaminergic signaling that in turn may direct the physiology of SPNs as well as the striatal related motor functions. Overall, our data reveal a novel LRRK2-based pathogenic mechanism of striatal dysfunction in PD.
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