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KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS.

KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS. JCI insight Akiyama, T., Zeng, Y., Guo, C., Gautier, O., Koepke, L., Lyons, H., Molotsky, E., Bombosch, J. S., Sianto, O., Ross, J. P., Hoang, P., Zhao, L., Spencer, C., Sumner, C. J., Monje, M., Day, J. W., Gitler, A. D. 2026

Abstract

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the survival motor neuron 1 (SMN1) gene leading to decreased SMN protein levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. SMN deficiency resulted in downregulation of kinesin heavy chain isoform 5A (KIF5A) in human neurons and in a mouse model of SMA. SMN associated with KIF5A mRNA and contributed to its stability. Reduced SMN levels impaired axon regeneration, which was rescued by KIF5A overexpression. Because KIF5A has also been connected to ALS, these findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as an SMN regulated factor. Our findings suggest SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases.

View details for DOI 10.1172/jci.insight.197941

View details for PubMedID 41885937