Abstract
Mutations in proline-rich transmembrane protein 2 (PRRT2) have been recently identified as the leading cause of a clinically heterogeneous group of neurological disorders sharing a paroxysmal nature, including paroxysmal kinesigenic dyskinesia and benign familial infantile seizures. To date, studies aimed at understanding its physiological functions in neurons have mainly focused on its ability to regulate neurotransmitter release and neuronal excitability. Here, we show that PRRT2 expression in non-neuronal cell lines inhibits cell motility and focal adhesion turnover, increases cell aggregation propensity, and promotes the protrusion of filopodia, all processes impinging on the actin cytoskeleton. In primary hippocampal neurons, PRRT2 silencing affects the synaptic content of filamentous actin and perturbs actin dynamics. This is accompanied by defects in the density and maturation of dendritic spines. We identified cofilin, an actin-binding protein abundantly expressed at the synaptic level, as the ultimate effector of PRRT2. Indeed, PRRT2 silencing unbalances cofilin activity leading to the formation of cofilin-actin rods along neurites. The expression of a cofilin phospho-mimetic mutant (cof-S3E) is able to rescue PRRT2-dependent defects in synapse density, spine number and morphology, but not the alterations observed in neurotransmitter release. Our data support a novel function of PRRT2 in the regulation of the synaptic actin cytoskeleton and in the formation of synaptic contacts.
Highlights
Introduction Mutations in the ProlineRich Transmembrane protein2 (PRRT2) gene were identified at the basis of a broad and heterogeneous spectrum of neurological conditions sharing a paroxysmal nature
PRRT2 silencing in hippocampal neurons in culture decreases the F-actin concentration at synapses Given the information gathered in cell lines, we evaluated in hippocampal neurons the effect of manipulation of PRRT2 levels on actin dynamics
Phosphorylation is required to recruit the endocytic adaptor protein dynamin[34], it is possible that PRRT2 influences focal adhesion disassembly and cell-extracellular matrix (ECM) adhesive properties, altering the migration capability
Summary
Introduction Mutations in the ProlineRich Transmembrane protein2 (PRRT2) gene were identified at the basis of a broad and heterogeneous spectrum of neurological conditions sharing a paroxysmal nature. It was recently described that PRRT2 regulates the membrane exposure and recovery from inactivation of the voltagegated sodium channels 1.2 and 1.6 subtypes responsible for the generation of action potentials in the axonal initial segment[5]. These results highlight a fundamental role of PRRT2 in stabilizing neuronal excitability[6], in-line with the hyperexcitability and paroxysmal manifestations observed in patients and mouse models in which PRRT2 is mutated[7,8]. This evidence suggests that, in addition to its role in the regulation of neuronal transmission, PRRT2 might have an unexpected role in neuronal cell architecture and, at the same time, in the control of neuronal motility and synapse formation
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