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

Akiyama, T.; Zeng, Y.; Guo, C.; Gautier, O.; Koepke, L. S.; Bombosch, J.; Sianto, O.; Ross, J. P.; Hoang, P. T.; Zhao, L. Y.; Spencer, C.; Monje, M.; Day, J. W.; Gitler, A. D.

doi:10.1101/2025.07.11.664426

bioRxiv · 10.1101/2025.07.11.664426

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

Akiyama, T.·Zeng, Y.·Guo, C.·Gautier, O.·Koepke, L. S.·Bombosch, J.·Sianto, O.·Ross, J. P.·Hoang, P. T.·Zhao, L. Y.·Spencer, C.·Monje, M.·Day, J. W.·Gitler, A. D.

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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 levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. Here, we demonstrate that SMN deficiency results in downregulation of KIF5A in human neurons and in a mouse model of SMA. We provide evidence that reduced SMN levels impair axon regeneration, which is rescued by KIF5A overexpression and that the RNA-binding protein SMN functions to stabilize KIF5A mRNA. These findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as a new SMN target. Our findings suggest SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases.

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Akiyama, T., Zeng, Y., Guo, C., Gautier, O., Koepke, L. S., Bombosch, J., Sianto, O., Ross, J. P., Hoang, P. T., Zhao, L. Y., Spencer, C., Monje, M., Day, J. W., Gitler, A. D.. 2025-07-13. KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS. https://doi.org/10.1101/2025.07.11.664426

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