KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons.

Autor:	Guerra San Juan I; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam and VU Medical Center, Amsterdam, The Netherlands.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.; Department of Human Genetics, Amsterdam University Medical Center, Amsterdam, The Netherlands., Brunner J; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam and VU Medical Center, Amsterdam, The Netherlands.; Department of Human Genetics, Amsterdam University Medical Center, Amsterdam, The Netherlands., Eggan K; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Toonen RF; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam and VU Medical Center, Amsterdam, The Netherlands.; Department of Human Genetics, Amsterdam University Medical Center, Amsterdam, The Netherlands., Verhage M; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam and VU Medical Center, Amsterdam, The Netherlands.; Department of Human Genetics, Amsterdam University Medical Center, Amsterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 11. Date of Electronic Publication: 2024 Sep 11.
DOI:	10.1101/2024.09.06.611684
Abstrakt:	Mutations in the microtubule binding motor protein, kinesin family member 5A (KIF5A), cause the fatal motor neuron disease, Amyotrophic Lateral Sclerosis. While KIF5 family members transport a variety of cargos along axons, it is still unclear which cargos are affected by KIF5A mutations. We generated KIF5A null mutant human motor neurons to investigate the impact of KIF5A loss on the transport of various cargoes and its effect on motor neuron function at two different timepoints in vitro . The absence of KIF5A resulted in reduced neurite complexity in young motor neurons (DIV14) and significant defects in axonal regeneration capacity at all developmental stages. KIF5A loss did not affect neurofilament transport but resulted in decreased mitochondria motility and anterograde speed at DIV42. More prominently, KIF5A depletion strongly reduced anterograde transport of SFPQ-associated RNA granules in DIV42 motor neuron axons. We conclude that KIF5A most prominently functions in human motor neurons to promote axonal regrowth after injury as well as to anterogradely transport mitochondria and, to a larger extent, SFPQ-associated RNA granules in a time-dependent manner. Competing Interests: Declaration of Interests K.E. is a cofounder of Q-State Biosciences, Quralis, Enclear Therapies and is group vice-president at BioMarin Pharmaceutical. The remaining authors declare no competing interests.
Databáze:	MEDLINE
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