Title

Arginine Methyltransferase Prmt8 Provides Cellular Stress Tolerance In Aging Motoneurons

Keywords

ADMA; Aging; CREB1; Motoneuron; Neurodegeneration; PRMT8

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.

Publication Date

8-29-2018

Publication Title

Journal of Neuroscience

Volume

38

Issue

35

Number of Pages

7683-7700

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1523/JNEUROSCI.3389-17.2018

Socpus ID

85052649921 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/85052649921

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