Arginine Methyltransferase PRMT8 Provides Cellular Stress Tolerance in Aging Motoneurons

Abstract

Aging contributes to cellular stress and neurodegeneration. Our understanding is limited regarding the tissue-restricted mechanisms providing protection in postmitotic cells throughout life. Here, we show that spinal cord motoneurons exhibit a high abundance of asymmetric dimethyl arginines (ADMAs) 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 postmitotic neurons. Male PRMT8 knock-out 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 cAMP response-element-binding protein 1 (CREB1) level. As a consequence, the expression of CREB1-mediated prosurvival and regeneration-associated immediate early genes is dysregulated in aging PRMT8 knock-out mice. The uncovered role of PRMT8 represents a novel mechanism of stress tolerance in long-lived postmitotic neurons and identifies PRMT8 as a tissue-specific therapeutic target in the prevention of motoneuron degeneration. Although most of the cells in our body have a very short lifespan, postmitotic 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 postmitotic neurons. Specifically, we identify protein arginine methyltransferase 8 (PRMT8) as a cell-type-restricted arginine methyltransferase in spinal cord motoneurons (MNs). PRMT8-dependent arginine methylation is 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.

A global map of the impact of deletion of Post-Translational Modification sites in genetic diseases

“…Methylation of FUS is required to bind the autophagy receptor p62 which in association with other proteins can control the aberrant accumulation of the granules [54]. Other studies have reported methylation as an important modification type in the accumulation and elimination of these toxic granules [55] supporting our predicted association with ALS ( Figure 2C). In a close look, Figure 5C shows FUS with methylation sites affected and non-affected by the ALS mutations, the former with the probability of being more pathogenic than regular methylation sites, measured using rps.…”

Deciphering the molecular mechanisms underlying the plasma membrane targeting of PRMT8

“…The PRMT8 protein has critical roles in numerous physiological functions, including in the brain and stem cells, in a variety of animals (9, 10, 12, 22, 23). In zebrafish, for example, PRMT8 has an extra N-terminal sequence, and shows brain-specific expression that is critical for the development of the zebrafish brain.…”

“…This enzyme has a unique N-terminal extended region that is involved in plasma membrane localization via myristoylation, and is suggested to regulate PRMT8 enzymatic activity (7, 8). It is a multifunctional protein with arginine methyl transferase and phospholipase D activities (9), localizes to both presynaptic and postsynaptic sites, and plays multiple roles in the brain, including in Purkinje cell morphology, perineuronal net formation in the visual cortex, fear learning in the hippocampus, and neuroprotection against age-related increases in cellular stress (9–12). Type I PRMTs may undergo oligomerization/dimerization through an interaction between the dimerization arm projecting off the β-barrel and the Rossman fold of another subunit (13).…”

Friend or foe—Post-translational modifications as regulators of phase separation and RNP granule dynamics

“…Arg-methylation appears to be especially relevant in terminally differentiated and long-lived neurons, e.g. motor neurons, which show tissue-specific expression of PRMT8 and require Arg-methylation for a proper stress response and for maintaining motor neuron health during aging (132). Suppression of aberrant RBP phase separation by Arg-methylation may be part of the protective mechanism, and hence it would be interesting to examine whether loss of PRMT8 promotes pathological RBP phase transitions and alters RNP granule dynamics and function in neurons.…”