The protein arginine methyltransferase PRMT5 regulates Aβ‐induced toxicity in human cells and Caenorhabditis elegans models of Alzheimer's disease

The protein arginine methyltransferase 5 (PRMT5) controls cell growth and apoptosis by catalyzing mono and symmetric dimethylation of arginine residues. In human brain tissue, PRMT5 is predominantly expressed in neuronal cells. There is evidence that PRMT5 provides protection against cell death, but the impact of PRMT5 on neuronal apoptosis during the evolution of Alzheimer's disease has not been tested. In the present study, we show that PRMT5 is down-regulated by β-amyloid (Aβ) in primary neurons and SH-SY5Y cells, and this is associated with the up-regulation of the PRMT5 target protein E2F-1. Furthermore, knockdown of PRMT5 in SH-SY5Y 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 PRMT5 depletion. More importantly, knockdown of PRMT5 resulted in more paralysis in a transgenic Caenorhabditis elegans strain CL2006, indicating that PRMT5 provides protection against Aβ toxicity in vivo. Collectively, our findings identify PRMT5 as a novel regulator of Aβ toxicity and suggest that strategies aimed at activating PRMT5 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.