Journal
NEURODEGENERATIVE DISEASES
Volume 13, Issue 2-3, Pages 64-68Publisher
KARGER
DOI: 10.1159/000354669
Keywords
Alzheimer's disease; Presenilin; Voltage-gated sodium channel
Categories
Funding
- NIA NIH HHS [P01 AG015379, R01 AG014713, R21 AG031483] Funding Source: Medline
- NINDS NIH HHS [R01 NS045860] Funding Source: Medline
Ask authors/readers for more resources
Background: Familial Alzheimer's disease (FAD) mutations in presenilin (PS) modulate PS/gamma-secretase activity and therefore contribute to AD pathogenesis. Previously, we found that PS/gamma-secretase cleaves voltage-gated sodium channel beta(2)-subunits (Na-v beta(2)), releases the intracellular domain of Na-v beta(2) (beta(2)-ICD), and thereby, increases intracellular sodium channel a-subunit Na(v)1.1 levels. Here, we tested whether FAD-linked PS1 mutations modulate Na-v beta(2) cleavages and Nav1.1 levels. Objective: It was the aim of this study to analyze the effects of PS1-linked FAD mutations on Na-v beta(2) processing and Nav1.1 levels in neuronal cells. Methods: We first generated B104 rat neuroblastoma cells stably expressing NavB2 and wild-type PS1 (wtPS1), PS1 with one of three FAD mutations (E280A, M146L or Delta E9), or PS1 with a non-FAD mutation (D333G). Na-v beta(2) processing and Nav1.1 protein and nnRNA levels were then analyzed by Western blot and real-time RT-PCR, respectively. Results: The FAD-linked E280A mutation significantly decreased PS/gamma-secretase-mediated processing of Na-v beta(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 Na-v channel alpha-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/gamma-secretase-mediated cleavage of Na-v beta(2) in neuronal cells. (C) 2013 S. Karger AG, Basel
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available