The E280A Presenilin Mutation Reduces Voltage-Gated Sodium Channel Levels in Neuronal Cells
Copyright policy )The E280A Presenilin Mutation Reduces Voltage-Gated Sodium Channel Levels in Neuronal Cells
<b><i>Background:</i></b> 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 β<sub>2</sub>-subunits (Na<sub>v</sub>β<sub>2</sub>), releases the intracellular domain of Na<sub>v</sub>β<sub>2</sub> (β<sub>2</sub>-ICD), and thereby, increases intracellular sodium channel α-subunit Na<sub>v</sub>1.1 levels. Here, we tested whether FAD-linked PS1 mutations modulate Na<sub>v</sub>β<sub>2</sub> cleavages and Na<sub>v</sub>1.1 levels. <b><i>Objective:</i></b> It was the aim of this study to analyze the effects of PS1-linked FAD mutations on Na<sub>v</sub>β<sub>2</sub> processing and Na<sub>v</sub>1.1 levels in neuronal cells. <b><i>Methods:</i></b> We first generated B104 rat neuroblastoma cells stably expressing Na<sub>v</sub>β<sub>2</sub> and wild-type PS1 (wtPS1), PS1 with one of three FAD mutations (E280A, M146L or ΔE9), or PS1 with a non-FAD mutation (D333G). Na<sub>v</sub>β<sub>2</sub> processing and Na<sub>v</sub>1.1 protein and mRNA levels were then analyzed by Western blot and real-time RT-PCR, respectively. <b><i>Results:</i></b> The FAD-linked E280A mutation significantly decreased PS/γ-secretase-mediated processing of Na<sub>v</sub>β<sub>2</sub> as compared to wtPS1 controls, both in cells and in a cell-free system. Na<sub>v</sub>1.1 mRNA and protein levels, as well as the surface levels of Na<sub>v</sub> channel α-subunits, were also significantly reduced in PS1(E280A) cells. <b><i>Conclusion:</i></b> Our data indicate that the FAD-linked PS1(E280A) mutation decreases Na<sub>v</sub> channel levels by partially inhibiting the PS/γ-secretase-mediated cleavage of Na<sub>v</sub>β<sub>2</sub> in neuronal cells.
- Massachusetts General Hospital United States
- Harvard University United States
Neurons, Reverse Transcriptase Polymerase Chain Reaction, Blotting, Western, Presenilins, Voltage-Gated Sodium Channels, Real-Time Polymerase Chain Reaction, Transfection, Rats, Mutation, Animals, Amyloid Precursor Protein Secretases, Cells, Cultured
Neurons, Reverse Transcriptase Polymerase Chain Reaction, Blotting, Western, Presenilins, Voltage-Gated Sodium Channels, Real-Time Polymerase Chain Reaction, Transfection, Rats, Mutation, Animals, Amyloid Precursor Protein Secretases, Cells, Cultured
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