1. Opposing roles of p38α-mediated phosphorylation and arginine methylation in driving TDP-43 proteinopathy
- Author
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Aaron D. Gitler, Nicholas J. Brandon, Korrie L. Mack, Hana M. Odeh, Thomas A. Ollerhead, Bo Lim Lee, Stephen J. Moss, Bradley Class, Ashkan Javaherian, James Shorter, John Dunlop, Alice Flynn Ford, Mari Aikio, Steven Finkbeiner, Heike J. Wobst, Ryan R. Cupo, Lauren E. Drake, Dean G. Brown, Ashmita Baral, Nicholas A. Castello, and Edward M. Barbieri
- Subjects
MAPK/ERK pathway ,Arginine ,Chemistry ,p38 mitogen-activated protein kinases ,Neurotoxicity ,nutritional and metabolic diseases ,Methylation ,medicine.disease ,nervous system diseases ,Cell biology ,Serine ,mental disorders ,medicine ,Phosphorylation ,Protein kinase A - Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder typically characterized by insoluble inclusions of hyperphosphorylated TDP-43. The mechanisms underlying toxic TDP-43 accumulation are not understood. Persistent activation of p38 mitogen-activated protein kinase (MAPK) is implicated in ALS. However, it is unclear how p38 MAPK affects TDP-43 proteinopathy. Here, we demonstrate that inhibition of p38α MAPK reduces pathological TDP-43 phosphorylation, aggregation, cytoplasmic mislocalization, and neurotoxicity. We establish that p38α MAPK phosphorylates TDP-43 at pathological serine 409/410 (S409/S410) and serine 292 (S292), which reduces TDP-43 liquid-liquid phase separation (LLPS) but allows pathological TDP-43 aggregation. Moreover, we show that protein arginine methyltransferase 1 methylates TDP-43 at R293. Importantly, S292 phosphorylation reduces R293 methylation, and R293 methylation reduces S409/S410 phosphorylation. R293 methylation permits TDP-43 LLPS and reduces pathological TDP-43 aggregation. Thus, strategies to reduce p38α-mediated TDP-43 phosphorylation and promote R293 methylation could have therapeutic utility for ALS and related TDP-43 proteinopathies.
- Published
- 2021
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