Binding and transport of SFPQ-RNA granules by KIF5A/KLC1 motors promotes axon survival

• Published in: The Journal of cell biology Vol. 220; no. 1
• Main Authors: Fukuda, Yusuke, Pazyra-Murphy, Maria F, Silagi, Elizabeth S, Tasdemir-Yilmaz, Ozge E, Li, Yihang, Rose, Lillian, Yeoh, Zoe C, Vangos, Nicholas E, Geffken, Ezekiel A, Seo, Hyuk-Soo, Adelmant, Guillaume, Bird, Gregory H, Walensky, Loren D, Marto, Jarrod A, Dhe-Paganon, Sirano, Segal, Rosalind A
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 04.01.2021
• Subjects: Amino Acid Motifs; Amino Acid Sequence; Animals; Axonal Transport; Axons; Axons - metabolism; Circuits; Cytoplasmic Granules - metabolism; Degeneration; Functional morphology; Ganglia, Spinal - metabolism; Granular materials; HEK293 Cells; Humans; Kinesin; Kinesins - metabolism; Microtubule-Associated Proteins; Mitochondria - metabolism; Mutation; Mutation - genetics; Neural networks; Neurological diseases; Neuroscience; Peptides - metabolism; Phosphorylation; Protein Binding; Proteins; PTB-Associated Splicing Factor - metabolism; Rats; Rats, Sprague-Dawley; Ribonucleic acid; RNA; RNA - metabolism; RNA biology; RNA transport; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-binding protein; Sensory Receptor Cells - metabolism; Survival; Trafficking; Translation
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.202005051

Complex neural circuitry requires stable connections formed by lengthy axons. To maintain these functional circuits, fast transport delivers RNAs to distal axons where they undergo local translation. However, the mechanism that enables long-distance transport of RNA granules is not yet understood. Here, we demonstrate that a complex containing RNA and the RNA-binding protein (RBP) SFPQ interacts selectively with a tetrameric kinesin containing the adaptor KLC1 and the motor KIF5A. We show that the binding of SFPQ to the KIF5A/KLC1 motor complex is required for axon survival and is impacted by KIF5A mutations that cause Charcot-Marie Tooth (CMT) disease. Moreover, therapeutic approaches that bypass the need for local translation of SFPQ-bound proteins prevent axon degeneration in CMT models. Collectively, these observations indicate that KIF5A-mediated SFPQ-RNA granule transport may be a key function disrupted in KIF5A-linked neurologic diseases and that replacing axonally translated proteins serves as a therapeutic approach to axonal degenerative disorders.