The E280A presenilin mutation reduces voltage-gated sodium channel levels in neuronal cells.
Neurodegener Dis
; 13(2-3): 64-68, 2014.
Article
en En
| MEDLINE
| ID: mdl-24217025
ABSTRACT
BACKGROUND:
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 ß2-subunits (Navß2), releases the intracellular domain of Navß2 (ß2-ICD), and thereby, increases intracellular sodium channel α-subunit Nav1.1 levels. Here, we tested whether FAD-linked PS1 mutations modulate Navß2 cleavages and Nav1.1 levels.OBJECTIVE:
It was the aim of this study to analyze the effects of PS1-linked FAD mutations on Navß2 processing and Nav1.1 levels in neuronal cells.METHODS:
We first generated B104 rat neuroblastoma cells stably expressing Navß2 and wild-type PS1 (wtPS1), PS1 with one of three FAD mutations (E280A, M146L or ΔE9), or PS1 with a non-FAD mutation (D333G). Navß2 processing and Nav1.1 protein and mRNA levels were then analyzed by Western blot and real-time RT-PCR, respectively.RESULTS:
The FAD-linked E280A mutation significantly decreased PS/γ-secretase-mediated processing of Navß2 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.CONCLUSION:
Our data indicate that the FAD-linked PS1(E280A) mutation decreases Nav channel levels by partially inhibiting the PS/γ-secretase-mediated cleavage of Navß2 in neuronal cells.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Presenilinas
/
Canales de Sodio Activados por Voltaje
/
Mutación
/
Neuronas
Límite:
Animals
Idioma:
En
Revista:
Neurodegener Dis
Asunto de la revista:
NEUROLOGIA
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos