The protein arginine methyltransferase PRMT 5 regulates Aβ‐induced toxicity in human cells and Caenorhabditis elegans models of Alzheimer's disease

The protein arginine methyltransferase 5 ( PRMT 5) controls cell growth and apoptosis by catalyzing mono and symmetric dimethylation of arginine residues. In human brain tissue, PRMT 5 is predominantly expressed in neuronal cells. There is evidence that PRMT 5 provides protection against cell death, but the impact of PRMT 5 on neuronal apoptosis during the evolution of Alzheimer's disease has not been tested. In the present study, we show that PRMT 5 is down‐regulated by β‐amyloid (Aβ) in primary neurons and SH ‐ SY 5Y cells, and this is associated with the up‐regulation of the PRMT 5 target protein E2F‐1. Furthermore, knockdown of PRMT 5 in SH ‐ SY 5Y cells over‐expressing the Swedish mutant form of human amyloid‐β precursor protein caused activation of E2F‐1/p53/Bax, NF ‐κB, and GSK ‐3β pathways, which coincided with increased apoptosis. Co‐depletion of E2F‐1 reduced the activation of p53/Bax, NF ‐κB, and GSK ‐3β, and limited cell apoptosis. In addition, inhibiting NF ‐κB and GSK ‐3β activity by specific inhibitors also attenuated cell apoptosis, suggesting that E2F‐1/ NF ‐κB/ GSK ‐3β pathways mediate for apoptosis induced by PRMT 5 depletion. More importantly, knockdown of PRMT 5 resulted in more paralysis in a transgenic Caenorhabditis elegans strain CL 2006, indicating that PRMT 5 provides protection against Aβ toxicity in vivo . Collectively, our findings identify PRMT 5 as a novel regulator of Aβ toxicity and suggest that strategies aimed at activating PRMT 5 in the neuron may represent a potential therapeutic approach for the prevention of Alzheimer's disease.We propose the following cascade for protein arginine methyltransferase 5 (PRMT5)‐mediated neuronal death: amyloid beta (Aβ) deposition decreases PRMT5 expression in neurons, which increases E2F‐1 expression – a PRMT5 target protein – and subsequently activates GSK‐3β and NF‐κB to induce caspase‐3‐dependent neuronal apoptosis. These findings might provide a strategy for the treatment of Alzheimer's disease.