Arginine methyltransferase PRMT8 provides cellular stress tolerance in aging motoneurons

Zoltan Simandi, Krisztian Pajer, Katalin Karolyi, Tatiana Sieler, Lu Lin Jiang, Zsuzsanna Kolostyak, Zsanett Sari, Zoltan Fekecs, Attila Pap, Andreas Patsalos, Gerardo Alvarado Contreras, Balint Reho, Zoltan Papp, Xiufang Guo, Attila Horvath, Greta Kiss, Zsolt Keresztessy, György Vámosi, James Hickman, Huaxi XuDorothee Dormann, Tibor Hortobagyi, Miklos Antal, Antal Nógrádi, Laszlo Nagy

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)7683-7700
Number of pages18
JournalJournal of Neuroscience
Volume38
Issue number35
DOIs
StatePublished - Aug 29 2018
Externally publishedYes

Fingerprint

Protein-Arginine N-Methyltransferases
Motor Neurons
Cyclic AMP Response Element-Binding Protein
Knockout Mice
Arginine
Neurons
Immediate-Early Genes
Double-Stranded DNA Breaks
Neuromuscular Junction
Conservation of Natural Resources
Methyltransferases
Muscle Strength
Post Translational Protein Processing
human PRMT2 protein
Regeneration
Spinal Cord
Enzymes

Keywords

  • ADMA
  • Aging
  • CREB1
  • Motoneuron
  • Neurodegeneration
  • PRMT8

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Arginine methyltransferase PRMT8 provides cellular stress tolerance in aging motoneurons. / Simandi, Zoltan; Pajer, Krisztian; Karolyi, Katalin; Sieler, Tatiana; Jiang, Lu Lin; Kolostyak, Zsuzsanna; Sari, Zsanett; Fekecs, Zoltan; Pap, Attila; Patsalos, Andreas; Contreras, Gerardo Alvarado; Reho, Balint; Papp, Zoltan; Guo, Xiufang; Horvath, Attila; Kiss, Greta; Keresztessy, Zsolt; Vámosi, György; Hickman, James; Xu, Huaxi; Dormann, Dorothee; Hortobagyi, Tibor; Antal, Miklos; Nógrádi, Antal; Nagy, Laszlo.

In: Journal of Neuroscience, Vol. 38, No. 35, 29.08.2018, p. 7683-7700.

Research output: Contribution to journalArticle

Simandi, Z, Pajer, K, Karolyi, K, Sieler, T, Jiang, LL, Kolostyak, Z, Sari, Z, Fekecs, Z, Pap, A, Patsalos, A, Contreras, GA, Reho, B, Papp, Z, Guo, X, Horvath, A, Kiss, G, Keresztessy, Z, Vámosi, G, Hickman, J, Xu, H, Dormann, D, Hortobagyi, T, Antal, M, Nógrádi, A & Nagy, L 2018, 'Arginine methyltransferase PRMT8 provides cellular stress tolerance in aging motoneurons', Journal of Neuroscience, vol. 38, no. 35, pp. 7683-7700. https://doi.org/10.1523/JNEUROSCI.3389-17.2018
Simandi, Zoltan ; Pajer, Krisztian ; Karolyi, Katalin ; Sieler, Tatiana ; Jiang, Lu Lin ; Kolostyak, Zsuzsanna ; Sari, Zsanett ; Fekecs, Zoltan ; Pap, Attila ; Patsalos, Andreas ; Contreras, Gerardo Alvarado ; Reho, Balint ; Papp, Zoltan ; Guo, Xiufang ; Horvath, Attila ; Kiss, Greta ; Keresztessy, Zsolt ; Vámosi, György ; Hickman, James ; Xu, Huaxi ; Dormann, Dorothee ; Hortobagyi, Tibor ; Antal, Miklos ; Nógrádi, Antal ; Nagy, Laszlo. / Arginine methyltransferase PRMT8 provides cellular stress tolerance in aging motoneurons. In: Journal of Neuroscience. 2018 ; Vol. 38, No. 35. pp. 7683-7700.
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AU - Simandi, Zoltan

AU - Pajer, Krisztian

AU - Karolyi, Katalin

AU - Sieler, Tatiana

AU - Jiang, Lu Lin

AU - Kolostyak, Zsuzsanna

AU - Sari, Zsanett

AU - Fekecs, Zoltan

AU - Pap, Attila

AU - Patsalos, Andreas

AU - Contreras, Gerardo Alvarado

AU - Reho, Balint

AU - Papp, Zoltan

AU - Guo, Xiufang

AU - Horvath, Attila

AU - Kiss, Greta

AU - Keresztessy, Zsolt

AU - Vámosi, György

AU - Hickman, James

AU - Xu, Huaxi

AU - Dormann, Dorothee

AU - Hortobagyi, Tibor

AU - Antal, Miklos

AU - Nógrádi, Antal

AU - Nagy, Laszlo

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N2 - 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.

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