Cell Death and Disease (Sep 2024)

Altered molecular and cellular mechanisms in KIF5A-associated neurodegenerative or neurodevelopmental disorders

  • Marta Cozzi,
  • Stefania Magri,
  • Barbara Tedesco,
  • Guglielmo Patelli,
  • Veronica Ferrari,
  • Elena Casarotto,
  • Marta Chierichetti,
  • Paola Pramaggiore,
  • Laura Cornaggia,
  • Margherita Piccolella,
  • Mariarita Galbiati,
  • Paola Rusmini,
  • Valeria Crippa,
  • Jessica Mandrioli,
  • Davide Pareyson,
  • Chiara Pisciotta,
  • Stefano D’Arrigo,
  • Antonia Ratti,
  • Lorenzo Nanetti,
  • Caterina Mariotti,
  • Elisa Sarto,
  • Viviana Pensato,
  • Cinzia Gellera,
  • Daniela Di Bella,
  • Riccardo M. Cristofani,
  • Franco Taroni,
  • Angelo Poletti

DOI
https://doi.org/10.1038/s41419-024-07096-5
Journal volume & issue
Vol. 15, no. 9
pp. 1 – 16

Abstract

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Abstract Mutations targeting distinct domains of the neuron-specific kinesin KIF5A associate with different neurodegenerative/neurodevelopmental disorders, but the molecular bases of this clinical heterogeneity are unknown. We characterised five key mutants covering the whole spectrum of KIF5A-related phenotypes: spastic paraplegia (SPG, R17Q and R280C), Charcot-Marie-Tooth disease (CMT, R864*), amyotrophic lateral sclerosis (ALS, N999Vfs*40), and neonatal intractable myoclonus (NEIMY, C975Vfs*73) KIF5A mutants. CMT-R864*-KIF5A and ALS-N999Vfs*40-KIF5A showed impaired autoinhibition and peripheral localisation accompanied by altered mitochondrial distribution, suggesting transport competence disruption. ALS-N999Vfs*40-KIF5A formed SQSTM1/p62-positive inclusions sequestering WT-KIF5A, indicating a gain of toxic function. SPG-R17Q-KIF5A and ALS-N999Vfs*40-KIF5A evidenced a shorter half-life compared to WT-KIF5A, and proteasomal blockage determined their accumulation into detergent-insoluble inclusions. Interestingly, SPG-R280C-KIF5A and ALS-N999Vfs*40-KIF5A both competed for degradation with proteasomal substrates. Finally, NEIMY-C975Vfs*73-KIF5A displayed a similar, but more severe aberrant behaviour compared to ALS-N999Vfs*40-KIF5A; these two mutants share an abnormal tail but cause disorders on the opposite end of KIF5A-linked phenotypic spectrum. Thus, our observations support the pathogenicity of novel KIF5A mutants, highlight abnormalities of recurrent variants, and demonstrate that both unique and shared mechanisms underpin KIF5A-related diseases.