Arginine methyltransferase PRMT8 provides cellular stress tolerance in aging motoneurons

Aging contributes to cellular stress and neurodegeneration. Our understanding is limited regarding the tissue-restricted mechanisms providing protection in post-mitotic cells throughout life. Here, we show that spinal cord motoneurons exhibit a high abundance of asymmetric dimethyl arginines (ADMA) and the presence of this posttranslational modification provides protection against environmental stress. We identify Protein aRginine MethylTransferase 8 (PRMT8) as a tissue-restricted enzyme responsible for proper ADMA level in post-mitotic neurons. Male PRMT8 knockout mice display decreased muscle strength with aging due to premature destabilization of neuromuscular junctions. Mechanistically, inhibition of methyltransferase activity or loss of PRMT8 results in accumulation of unrepaired DNA double-stranded breaks and decrease in the CREB1 level. As a consequence, expression of CREB1-mediated pro-survival and regeneration-associated immediate early genes are dysregulated in aging PRMT8 knockout mice. The uncovered role of PRMT8 represents a novel mechanism of stress tolerance in long-lived post-mitotic neurons and identifies PRMT8 as a tissue-specific therapeutic target in the prevention of motoneuron degeneration. SIGNIFICANCE STATEMENT While most of the cells in our body have a very short lifespan, post-mitotic neurons must survive for many decades. Longevity of a cell within the organism depends on its ability to properly regulate signaling pathways that counteract perturbations, such as DNA damage, oxidative stress or protein misfolding. Here we provide evidence that tissue-specific regulators of stress tolerance exist in post-mitotic neurons. Specifically, we identify Protein Arginine Methyltransferase 8 (PRMT8) as a cell-type restricted arginine methyltransferase in spinal cord motoneurons. PRMT8-dependent arginine methylationis required for neuroprotection against age-related increased of cellular stress. Tissue-restricted expression and the enzymatic activity of PRMT8 make it an attractive target for drug development to delay the onset of neurodegenerative disorders.