Cell Reports (Jan 2025)
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 Castello,
- Ashmita Baral,
- Jenna N. Beyer,
- Mohd A. Najar,
- John Dunlop,
- Aaron D. Gitler,
- Ashkan Javaherian,
- Julia A. Kaye,
- George M. Burslem,
- Dean G. Brown,
- Christopher J. Donnelly,
- Steven Finkbeiner,
- Stephen J. Moss,
- Nicholas J. Brandon,
- James Shorter
Affiliations
- Mari Aikio
- AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University, Boston, MA 02111, USA; Neumora Therapeutics, Watertown, MA 02472, USA
- Hana M. Odeh
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Heike J. Wobst
- Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA 02451, USA
- Bo Lim Lee
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Úna Chan
- Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA
- Jocelyn C. Mauna
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; LiveLikeLou Center for ALS Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; University of Pittsburgh Brain Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- Korrie L. Mack
- Neumora Therapeutics, Watertown, MA 02472, USA; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Bradley Class
- Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA 02451, USA
- Thomas A. Ollerhead
- AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University, Boston, MA 02111, USA
- Alice F. Ford
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Edward M. Barbieri
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Ryan R. Cupo
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Lauren E. Drake
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Joshua L. Smalley
- AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University, Boston, MA 02111, USA
- Yuan-Ta Lin
- Neumora Therapeutics, Watertown, MA 02472, USA
- Stephanie Lam
- Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA
- Reuben Thomas
- Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA
- Nicholas Castello
- Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA
- Ashmita Baral
- Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA
- Jenna N. Beyer
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Mohd A. Najar
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- John Dunlop
- Neumora Therapeutics, Watertown, MA 02472, USA; Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA 02451, USA
- Aaron D. Gitler
- Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
- Ashkan Javaherian
- Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA
- Julia A. Kaye
- Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA; Taube/Koret Center for Neurodegenerative Disease Research, Gladstone Institutes, San Francisco, CA 94158, USA
- George M. Burslem
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Dean G. Brown
- Hit Discovery, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA 02451, USA
- Christopher J. Donnelly
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; LiveLikeLou Center for ALS Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; University of Pittsburgh Brain Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- Steven Finkbeiner
- Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA; Taube/Koret Center for Neurodegenerative Disease Research, Gladstone Institutes, San Francisco, CA 94158, USA; Deparments of Neurology and Physiology, Neuroscience Graduate Program and Biomedical Sciences Program, University of California, San Francisco, San Francisco, CA 94158, USA
- Stephen J. Moss
- AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University, Boston, MA 02111, USA
- Nicholas J. Brandon
- AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University, Boston, MA 02111, USA; Neumora Therapeutics, Watertown, MA 02472, USA; Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA 02451, USA
- James Shorter
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author
- Journal volume & issue
-
Vol. 44,
no. 1
p. 115205
Abstract
Summary: 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.
