Dataset Information

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

ACCESS DATA

Publications

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

Visanji Naomi P NP Wislet-Gendebien Sabine S Oschipok Loren W LW Zhang Gang G Aubert Isabelle I Fraser Paul E PE Tandon Anurag A

The Journal of biological chemistry 20110817 41

In the healthy brain, less than 5% of α-synuclein (α-syn) is phosphorylated at serine 129 (Ser(P)-129). However, within Parkinson disease (PD) Lewy bodies, 89% of α-syn is Ser(P)-129. The effects of Ser(P)-129 modification on α-syn distribution and solubility are poorly understood. As α-syn normally exists in both membrane-bound and cytosolic compartments, we examined the binding and dissociation of Ser(P)-129 α-syn and analyzed the effects of manipulating Ser(P)-129 levels on α-syn membrane int ...[more]

PMID: 21849493

Similar Datasets

Project description:Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene for which no therapies are available. HTT mutation causes protein misfolding and aggregation, preferentially affecting medium spiny neurons (MSNs) of the basal ganglia. Transcriptional perturbations in synaptic genes and neuroinflammation are key processes that precede MSN dysfunction and motor symptom onset. Understanding the interplay between these processes is crucial to develop effective therapeutic strategies to treat HD. We investigated the role of protein kinase CK2α', a kinase upregulated in MSNs in HD and previously associated with Parkinson's disease (PD), in the regulation of neuroinflammation and synaptic function in HD. We used the heterozygous knock-in zQ175 HD mouse model and compared that to zQ175 mice lacking one allele of CK2α' (zQ175:CK2α'(±)). CK2α' haploinsufficiency in zQ175 mice resulted in decreased levels of pro-inflammatory cytokines, HTT aggregation, astrogliosis and transcriptional alterations of synaptic genes related to glutamatergic signaling. zQ175:CK2α'(±) mice also presented increased frequency of striatal miniature excitatory postsynaptic currents (mEPSCs), an indicator of synaptic activity, and improved motor coordination compared to zQ175 mice. Neuropathological and phenotypic changes mediated by CK2α' were connected to alpha-synuclein (α-syn) dysregulation and correlated with differences in α-syn serine 129 phosphorylation (pS129-α-syn), a post-translational modification involved in α-synucleinopathy and shown to be regulated by CK2 in PD. pS129-α-syn was increased in the nuclei of MSNs in zQ175 mice and in the striatum of patients with HD, and it decreased in zQ175:CK2α'(±) mice. Collectively, our data established a novel connection between CK2α', neuroinflammation and synaptic gene dysregulation with synucleinopathy in HD and suggested common molecular mechanisms of neurodegeneration between HD and PD. Our results also support CK2α' inhibition as a potential therapeutic strategy to modulate neuronal function and neuroprotection in HD.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets