Proline-rich transmembrane protein 2 (PRRT2) regulates the actin cytoskeleton during synaptogenesis: Cell Death and Disease

E. Savino, R.I. Cervigni, M. Povolo, A. Stefanetti, D. Ferrante, P. Valente, A. Corradi, F. Benfenati, F.C. Guarnieri, F. Valtorta

Research output: Contribution to journalArticlepeer-review

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. © 2020, The Author(s).
Original languageEnglish
JournalCell Death Dis.
Volume11
Issue number10
DOIs
Publication statusPublished - 2020

Keywords

  • actin
  • cofilin
  • F actin
  • focal adhesion kinase
  • G actin
  • membrane protein
  • phalloidin
  • proline rich transmembrane protein 2
  • protein Cdc42
  • short hairpin RNA
  • unclassified drug
  • actin filament
  • actin polymerization
  • amino terminal sequence
  • animal cell
  • Article
  • cell adhesion
  • cell aggregation
  • cell density
  • cell maturation
  • cell migration
  • cell motility
  • cell structure
  • comparative study
  • controlled study
  • cytoskeleton
  • dendritic spine
  • ectopic expression
  • excitatory postsynaptic potential
  • extracellular matrix
  • female
  • focal adhesion
  • genetic transfection
  • HEK293T cell line
  • human
  • human cell
  • immunofluorescence test
  • mouse
  • nonhuman
  • priority journal
  • protein expression
  • protein phosphorylation
  • quantitative analysis
  • synaptic transmission
  • synaptogenesis
  • time lapse imaging
  • ultracentrifugation
  • Western blotting
  • whole cell patch clamp
  • wound healing assay

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