Peer-Reviewed Publication
Cell Rep2025;44(1):115205.January 28, 2025Journal Article
Opposing roles of p38α-mediated phosphorylation and PRMT1-mediated arginine methylation in driving TDP-43 proteinopathy.
Mari Aikio1, Hana M Odeh2, Heike J Wobst3, Bo Lim Lee2, Úna Chan4, Jocelyn C Mauna5, Korrie L Mack6, Bradley Class3, Thomas A Ollerhead7, Alice F Ford8, Edward M Barbieri2, Ryan R Cupo9, Lauren E Drake2, Joshua L Smalley7, Yuan-Ta Lin10, Stephanie Lam4, Reuben Thomas11, Nicholas Castello4, Ashmita Baral4, Jenna N Beyer12, Mohd A Najar2, John Dunlop13, Aaron D Gitler14, Ashkan Javaherian4, Julia A Kaye15, George M Burslem16, Dean G Brown17, Christopher J Donnelly5, Steven Finkbeiner18, Stephen J Moss7, Nicholas J Brandon19, James Shorter20
1AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University, Boston, MA 02111, USA; Neumora Therapeutics, Watertown, MA 02472, USA.
2Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA 02451, USA.
4Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA.
5Department 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.
6Neumora 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.
7AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University, Boston, MA 02111, USA.
8Department 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.
9Department 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.
10Neumora Therapeutics, Watertown, MA 02472, USA.
11Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA.
12Department 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.
13Neumora Therapeutics, Watertown, MA 02472, USA; Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA 02451, USA.
14Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
15Center 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.
16Department 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.
17Hit Discovery, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA 02451, USA.
18Center 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.
19AstraZeneca-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.
20Department 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. Electronic address: jshorter@pennmedicine.upenn.edu.
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 sho…
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