Effect of Ser-129 phosphorylation on interaction of ?-synuclein with synaptic and cellular membranes.

ABSTRACT: In the healthy brain, less than 5% of ?-synuclein (?-syn) is phosphorylated at serine 129 (Ser(P)-129). However, within Parkinson disease (PD) Lewy bodies, 89% of ?-syn is Ser(P)-129. The effects of Ser(P)-129 modification on ?-syn distribution and solubility are poorly understood. As ?-syn normally exists in both membrane-bound and cytosolic compartments, we examined the binding and dissociation of Ser(P)-129 ?-syn and analyzed the effects of manipulating Ser(P)-129 levels on ?-syn membrane interactions using synaptosomal membranes and neural precursor cells from ?-syn-deficient mice or transgenic mice expressing human ?-syn. We first evaluated the recovery of the Ser(P)-129 epitope following either ?-syn membrane binding or dissociation. We demonstrate a rapid turnover of Ser(P)-129 during both binding to and dissociation from synaptic membranes. Although the membrane binding of WT ?-syn was insensitive to modulation of Ser(P)-129 levels by multiple strategies (the use of phosphomimic S129D and nonphosphorylated S129A ?-syn mutants; by enzymatic dephosphorylation of Ser(P)-129 or proteasome inhibitor-induced elevation in Ser(P)-129; or by inhibition or stable overexpression of PLK2), PD mutant Ser(P)-129 ?-syn showed a preferential membrane association compared with WT Ser(P)-129 ?-syn. Collectively, these data suggest that phosphorylation at Ser-129 is dynamic and that the subcellular distribution of ?-syn bearing PD-linked mutations, A30P or A53T, is influenced by the phosphorylation state of Ser-129.

SUBMITTER: Visanji NP 

PROVIDER: S-EPMC3195582 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature