2. Academic Validation
  3. Identification of p38 MAPK inhibition as a neuroprotective strategy for combinatorial SMA therapy

Identification of p38 MAPK inhibition as a neuroprotective strategy for combinatorial SMA therapy

  • EMBO Mol Med. 2025 Oct;17(10):2762-2786. doi: 10.1038/s44321-025-00303-6.
Maria J Carlini 1,  Jorge Espinoza-Derout 2,  Meaghan Van Alstyne 1 2,  Sarah Tisdale 1 2,  Eileen Workman 2,  Marina K Triplett 2,  Ivan Tattoli 2,  Shubhi Yadav 1,  Christopher E Henderson 2 3,  D Martin Watterson 4,  Livio Pellizzoni 5 6 7
Affiliations

Affiliations

  • 1 Department of Neurology, Columbia University, New York, NY, 10032, USA.
  • 2 Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA.
  • 3 Center for Motor Neuron Biology and Disease, Columbia University, New York, NY, 10032, USA.
  • 4 Department of Pharmacology, Northwestern University, Chicago, IL, 60611, USA.
  • 5 Department of Neurology, Columbia University, New York, NY, 10032, USA. [email protected].
  • 6 Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA. [email protected].
  • 7 Center for Motor Neuron Biology and Disease, Columbia University, New York, NY, 10032, USA. [email protected].
PMID: 40926051 DOI: 10.1038/s44321-025-00303-6
Abstract

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by ubiquitous deficiency in the SMN protein. The identification of disease modifiers is key to understanding pathogenic mechanisms and broadening the range of targets for developing SMA therapies that complement SMN upregulation. Here, we report a cell-based screen that identified inhibitors of p38 mitogen-activated protein kinase (p38 MAPK) as suppressors of proliferation defects induced by SMN deficiency in mouse fibroblasts. We further show that SMN deficiency induces p38 MAPK activation and that pharmacological inhibition of this pathway improves motor function in SMA mice through SMN-independent neuroprotective effects. Using a highly optimized p38 MAPK Inhibitor (MW150) and combinatorial treatment in SMA mice, we observed synergistic enhancement of the phenotypic benefit induced by either MW150 or an SMN-inducing drug alone. By promoting motor neuron survival, pharmacological inhibition of p38 MAPK synergizes with SMN induction and enables enhanced synaptic rewiring of motor neurons within sensory-motor spinal circuits. These studies identify the p38 MAPK pathway as a therapeutic target and MW150 as a neuroprotective drug for combination therapy in SMA.

Keywords

Combination Therapy; Neuroprotection; Spinal Muscular Atrophy (SMA); Survival Motor Neuron (SMN); p38 Mitogen-Activated Protein Kinase (p38 MAPK).

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