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Inhibiting specific kinases in the p38 MAPK pathway module to treat different genetic forms of ALS

Award Number: R56NS146375
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Inhibiting specific kinases in the p38 MAPK pathway module to treat different genetic forms of ALS - PROJECT SUMMARY ABSTRACT Axonal degeneration has been established as an early and crucial pathological event driving the devastating clinical symptoms of amyotrophic lateral sclerosis (ALS), but the underlying mechanisms remain elusive. Notably, numerous independent studies have documented deficits in fast axonal transport (FAT), a crucial cellular process sustaining axonal homeostasis, in nerves from living ALS-affected patients and familial ALS (fALS) models. Genetic data linking loss-of-function mutations in genes that encode subunits of molecular motors (i.e., KIF5A) to specific fALS variants demonstrated that deficits in FAT are sufficient to cause axonopathy, but how other functionally unrelated fALS-linked proteins elicit such deficits remained unclear. Using a unique ex vivo axonal preparation, we found that mutant forms of superoxide dismutase 1 (mSOD1), profilin-1 (mPFN1), and other fALS-linked proteins inhibit FAT by promoting abnormal activation of p38 MAPKs, downstream kinase components of the three-tiered p38 MAPK pathway module. We also identified p38a as the specific p38 MAPK isoform activated by mSOD1 in vivo and revealed both kinesin-1 and neurofilaments as axonal proteins undergoing aberrant phosphorylation in the presence of mSOD1. The essential role of FAT in axonal function and health prompted us to investigatd a potential contribution of p38a to mSOD1-induced axonopathy in vivo. Remarkably, we found that ubiquitous, genetically-based attenuation of p38a signaling can prevent or delay degeneration of spinal cord axons in SOD1G93A mice, a fALS model that faithfully recapitulates the axonopathic phenotype characteristic of ALS. These findings provide a strong premise for the hypothesis that heightened p38a activation drives the onset and progression of ALS-like phenotypes elicited by mSOD1 in vivo. We have assembled a strong multidisciplinary team of researchers with established track records in the fields of ALS, axon biology, kinase signal transduction, pharmacology, and neuroproteomics to address this hypothesis through highly complementary, properly-powered genetic (Aim 1) and pharmacological (Aim 2) preclinical studies of high therapeutic relevance. Enhancing the conceptual innovation and overall impact of this revised proposal, Aim 3 will address a critical gap in our understanding of how two functionally unrelated fALS-linked proteins promote abnormal activation of p38 MAPKs and axonopathy. Specifically, we will employ quantitative phosphoproteomics to identify proteins whose phosphorylation state is affected by mSOD1 and mPFN1 in a p38a-dependent manner in vivo. Collectively, outcomes from this proposal will advance the field of ALS research by rigorously determining p38a contributions to ALS-like neuropathological outcomes elicited by mSOD1 in vivo, and by uncovering shared and distinct molecular components of pathogenic pathways linking two unrelated fALS-linked proteins to aberrant p38 MAPK activation and axonopathy.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $528,643 )
2026	2026	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/27/2026	NEW	$528,643
														Subtotal = $528,643

Grand Total All Awards = $528,643

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Inhibiting specific kinases in the p38 MAPK pathway module to treat different genetic forms of ALS

Award Number: R56NS146375

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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