Opposing roles of p38α-mediated phosphorylation and PRMT1-mediated arginine methylation in driving TDP-43 proteinopathy
Mari Aikio, Hana M. Odeh, Heike J. Wobst, Bo Lim Lee, Úna Chan, Jocelyn C. Mauna, Korrie L. Mack, Bradley Class, Thomas A. Ollerhead, Alice F. Ford, Edward M. Barbieri, Ryan R. Cupo, Lauren E. Drake, Joshua L. Smalley, Yuan-Ta Lin, Stephanie Lam, Reuben Thomas, Nicholas A. Castello, Ashmita Baral, Jenna N. Beyer, Mohd Altaf Najar, John Dunlop, Aaron D. Gitler, Ashkan Javaherian, Julia Kaye, George M. Burslem, Dean G. Brown, Christopher J. Donnelly, Steven Finkbeiner, Stephen J. Moss, Nicholas J. Brandon, James Shorter
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating 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 show that p38α MAPK inhibition reduces pathological TDP-43 phosphorylation, aggregation, cytoplasmic mislocalization, and neurotoxicity. Remarkably, p38α MAPK inhibition mitigates aberrant TDP-43 phenotypes in diverse ALS patient-derived motor neurons. p38α MAPK phosphorylates TDP-43 at pathological S409/S410 and S292, which reduces TDP-43 liquid-liquid phase separation (LLPS) but allows pathological TDP-43 aggregation. Moreover, we establish that PRMT1 methylates TDP-43 at R293. Importantly, S292 phosphorylation reduces R293 methylation, and R293 methylation reduces S409/S410 phosphorylation. Notably, R293 methylation permits TDP-43 LLPS and reduces pathological TDP-43 aggregation. Thus, strategies to reduce p38α-mediated TDP-43 phosphorylation and promote PRMT1-mediated R293 methylation could have therapeutic utility for ALS and related TDP-43 proteinopathies.