KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons
Mutations in the microtubule-binding motor protein kinesin 5 A (KIF5A) are implicated in several adult-onset motor neuron diseases, including Amyotrophic Lateral Sclerosis, Spastic Paraplegia Type 10 and Charcot-Marie-Tooth Disease Type 2. While KIF5 family members transport a variety of cargos alon...
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| Language: | English |
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Elsevier
2025-01-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996124003619 |
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| author | Irune Guerra San Juan Jessie W. Brunner Kevin Eggan Ruud F. Toonen Matthijs Verhage |
| author_facet | Irune Guerra San Juan Jessie W. Brunner Kevin Eggan Ruud F. Toonen Matthijs Verhage |
| author_sort | Irune Guerra San Juan |
| collection | DOAJ |
| description | Mutations in the microtubule-binding motor protein kinesin 5 A (KIF5A) are implicated in several adult-onset motor neuron diseases, including Amyotrophic Lateral Sclerosis, Spastic Paraplegia Type 10 and Charcot-Marie-Tooth Disease Type 2. While KIF5 family members transport a variety of cargos along axons, the specific cargos affected by KIF5A mutations remain poorly understood. Here, we generated KIF5Anull mutant human motor neurons and analyzed the impact on axonal transport and motor neuron outgrowth and regeneration in vitro. KIF5A deficiency caused reduced neurite complexity in young neurons (DIV14) and defects in axonal regeneration. KIF5A deficiency did not affect neurofilament transport but impaired mitochondrial motility and anterograde speed at DIV42. Notably, KIF5A deficiency strongly reduced anterograde transport of splicing factor proline/glutamine-rich (SFPQ)-associated RNA granules in DIV42 axons. Hence, KIF5A plays a critical role in promoting axonal regrowth after injury and in driving the anterograde transport of mitochondria and especially SFPQ-associated RNA granules in mature neurons. |
| format | Article |
| id | doaj-art-eca09670f2be4868b2736385fe27ea62 |
| institution | OA Journals |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-eca09670f2be4868b2736385fe27ea622025-08-20T02:26:27ZengElsevierNeurobiology of Disease1095-953X2025-01-0120410675910.1016/j.nbd.2024.106759KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neuronsIrune Guerra San Juan0Jessie W. Brunner1Kevin Eggan2Ruud F. Toonen3Matthijs Verhage4Department 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; Corresponding authors at: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam and VU Medical Center, Amsterdam, the Netherlands.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 NetherlandsDepartment of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USADepartment 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 NetherlandsDepartment 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; Corresponding authors at: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam and VU Medical Center, Amsterdam, the Netherlands.Mutations in the microtubule-binding motor protein kinesin 5 A (KIF5A) are implicated in several adult-onset motor neuron diseases, including Amyotrophic Lateral Sclerosis, Spastic Paraplegia Type 10 and Charcot-Marie-Tooth Disease Type 2. While KIF5 family members transport a variety of cargos along axons, the specific cargos affected by KIF5A mutations remain poorly understood. Here, we generated KIF5Anull mutant human motor neurons and analyzed the impact on axonal transport and motor neuron outgrowth and regeneration in vitro. KIF5A deficiency caused reduced neurite complexity in young neurons (DIV14) and defects in axonal regeneration. KIF5A deficiency did not affect neurofilament transport but impaired mitochondrial motility and anterograde speed at DIV42. Notably, KIF5A deficiency strongly reduced anterograde transport of splicing factor proline/glutamine-rich (SFPQ)-associated RNA granules in DIV42 axons. Hence, KIF5A plays a critical role in promoting axonal regrowth after injury and in driving the anterograde transport of mitochondria and especially SFPQ-associated RNA granules in mature neurons.http://www.sciencedirect.com/science/article/pii/S0969996124003619KIF5AKinesinsMotor neuronsHuman neuronsAxonal transportMitochondria |
| spellingShingle | Irune Guerra San Juan Jessie W. Brunner Kevin Eggan Ruud F. Toonen Matthijs Verhage KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons Neurobiology of Disease KIF5A Kinesins Motor neurons Human neurons Axonal transport Mitochondria |
| title | KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons |
| title_full | KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons |
| title_fullStr | KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons |
| title_full_unstemmed | KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons |
| title_short | KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons |
| title_sort | kif5a regulates axonal repair and time dependent axonal transport of sfpq granules and mitochondria in human motor neurons |
| topic | KIF5A Kinesins Motor neurons Human neurons Axonal transport Mitochondria |
| url | http://www.sciencedirect.com/science/article/pii/S0969996124003619 |
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