PT  - JOURNAL ARTICLE
AU  - Zoltan Simandi
AU  - Krisztian Pajer
AU  - Katalin Karolyi
AU  - Tatiana Sieler
AU  - Lu-Lin Jiang
AU  - Zsuzsanna Kolostyak
AU  - Zsanett Sari
AU  - Zoltan Fekecs
AU  - Attila Pap
AU  - Andreas Patsalos
AU  - Gerardo Alvarado Contreras
AU  - Balint Reho
AU  - Zoltan Papp
AU  - Xiufang Guo
AU  - Attila Horvath
AU  - Greta Kiss
AU  - Zsolt Keresztessy
AU  - György Vámosi
AU  - James Hickman
AU  - Huaxi Xu
AU  - Dorothee Dormann
AU  - Tibor Hortobagyi
AU  - Miklos Antal
AU  - Antal Nógrádi
AU  - Laszlo Nagy
TI  - Arginine Methyltransferase PRMT8 Provides Cellular Stress Tolerance in Aging Motoneurons
AID  - 10.1523/JNEUROSCI.3389-17.2018
DP  - 2018 Aug 29
TA  - The Journal of Neuroscience
PG  - 7683--7700
VI  - 38
IP  - 35
4099  - http://www.jneurosci.org/content/38/35/7683.short
4100  - http://www.jneurosci.org/content/38/35/7683.full
SO  - J. Neurosci.2018 Aug 29; 38
AB  - 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.SIGNIFICANCE STATEMENT 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.