Referenced in: none

Automatically associated channels: Nav1.1

Title: The E280A presenilin mutation reduces voltage-gated sodium channel levels in neuronal cells.

Authors: Doo Yeon Kim, Mary H Wertz, Vivek Gautam, Carla D'Avanzo, Raja Bhattacharyya, Dora M Kovacs

Journal, date & volume: Neurodegener Dis, 2014 , 13, 64-8

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24217025

Abstract
Familial Alzheimer's disease (FAD) mutations in presenilin (PS) modulate PS/γ-secretase activity and therefore contribute to AD pathogenesis. Previously, we found that PS/γ-secretase cleaves voltage-gated sodium channel β2-subunits (Navβ2), releases the intracellular domain of Navβ2 (β2-ICD), and thereby, increases intracellular sodium channel α-subunit Nav1.1 levels. Here, we tested whether FAD-linked PS1 mutations modulate Navβ2 cleavages and Nav1.1 levels.It was the aim of this study to analyze the effects of PS1-linked FAD mutations on Navβ2 processing and Nav1.1 levels in neuronal cells.We first generated B104 rat neuroblastoma cells stably expressing Navβ2 and wild-type PS1 (wtPS1), PS1 with one of three FAD mutations (E280A, M146L or ΔE9), or PS1 with a non-FAD mutation (D333G). Navβ2 processing and Nav1.1 protein and mRNA levels were then analyzed by Western blot and real-time RT-PCR, respectively.The FAD-linked E280A mutation significantly decreased PS/γ-secretase-mediated processing of Navβ2 as compared to wtPS1 controls, both in cells and in a cell-free system. Nav1.1 mRNA and protein levels, as well as the surface levels of Nav channel α-subunits, were also significantly reduced in PS1(E280A) cells.Our data indicate that the FAD-linked PS1(E280A) mutation decreases Nav channel levels by partially inhibiting the PS/γ-secretase-mediated cleavage of Navβ2 in neuronal cells.