Leucine ‐rich repeat kinase 2 phosphorylation on synapsin I regulates glutamate release at pre‐synaptic sites

Leucine ‐rich repeat kinase 2 (LRRK2) is a multidomain protein extensively studied being mutated in familial Parkinson's disease. Because its kinase activity is a highly promising pharmacological target for the treatment of the disease, the identification of LRRK2 substrates is crucial to understand the c onsequence of LRRK2 kinase inhibition. Here we demonstrated that synapsin I is phosphorylated by LRRK2 at threonine 337 and 339. Functionally, we provided several evidences that LRRK2‐dependent phosphorylation of synapsin I impacts glutamate release and synaptic vesicles dynamics. Since LRRK2 muta tions display increased kinase activity, our results may imply that mutant LRRK2 impair synaptic vesicle dynamics via aberrant phosphorylation of synapsinI. AbstractLeucine ‐rich repeat kinase 2 (LRRK2) is a large multidomain scaffolding protein with kinase and GTPase activities involved in synaptic vesicle (SV) dynamics. While its role in Parkinson’s disease has been largely investigated, little is known about LRRK2 physiological role and until now few proteins ha ve been described as substrates. We have previously demonstrated that LRRK2 through its WD40 domain interacts with synapsin I, an important SV‐associated phosphoprotein involved in neuronal development and in the regulation of neurotransmitter release. To test whether synapsin I is substrate for L RRK2 and characterize the properties of its phosphorylation, we used invitro kinase and binding assays as well as c...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: Original Article Source Type: research