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

ABSTRACT: Familial Alzheimer's disease (FAD) mutations in presenilin (PS) modulate PS/?-secretase activity and therefore contribute to AD pathogenesis. Previously, we found that PS/?-secretase cleaves voltage-gated sodium channel ?2-subunits (Nav?2), releases the intracellular domain of Nav?2 (?2-ICD), and thereby, increases intracellular sodium channel ?-subunit Nav1.1 levels. Here, we tested whether FAD-linked PS1 mutations modulate Nav?2 cleavages and Nav1.1 levels.It was the aim of this study to analyze the effects of PS1-linked FAD mutations on Nav?2 processing and Nav1.1 levels in neuronal cells.We first generated B104 rat neuroblastoma cells stably expressing Nav?2 and wild-type PS1 (wtPS1), PS1 with one of three FAD mutations (E280A, M146L or ?E9), or PS1 with a non-FAD mutation (D333G). Nav?2 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/?-secretase-mediated processing of Nav?2 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 ?-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/?-secretase-mediated cleavage of Nav?2 in neuronal cells.

SUBMITTER: Kim DY 

PROVIDER: S-EPMC3940070 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature