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.

Altered molecular and cellular mechanisms in KIF5A-associated neurodegenerative or neurodevelopmental disorders / Cozzi, Marta; Magri, Stefania; Tedesco, Barbara; Patelli, Guglielmo; Ferrari, Veronica; Casarotto, Elena; Chierichetti, Marta; Pramaggiore, Paola; Cornaggia, Laura; Piccolella, Margherita; Galbiati, Mariarita; Rusmini, Paola; Crippa, Valeria; Mandrioli, Jessica; Pareyson, Davide; Pisciotta, Chiara; D'Arrigo, Stefano; Ratti, Antonia; Nanetti, Lorenzo; Mariotti, Caterina; Sarto, Elisa; Pensato, Viviana; Gellera, Cinzia; Di Bella, Daniela; Cristofani, Riccardo M.; Taroni, Franco; Poletti, Angelo. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 15:9(2024), pp. 1-16. [10.1038/s41419-024-07096-5]

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

Mandrioli, Jessica;
2024

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.
2024
15
9
1
16
Altered molecular and cellular mechanisms in KIF5A-associated neurodegenerative or neurodevelopmental disorders / Cozzi, Marta; Magri, Stefania; Tedesco, Barbara; Patelli, Guglielmo; Ferrari, Veronica; Casarotto, Elena; Chierichetti, Marta; Pramaggiore, Paola; Cornaggia, Laura; Piccolella, Margherita; Galbiati, Mariarita; Rusmini, Paola; Crippa, Valeria; Mandrioli, Jessica; Pareyson, Davide; Pisciotta, Chiara; D'Arrigo, Stefano; Ratti, Antonia; Nanetti, Lorenzo; Mariotti, Caterina; Sarto, Elisa; Pensato, Viviana; Gellera, Cinzia; Di Bella, Daniela; Cristofani, Riccardo M.; Taroni, Franco; Poletti, Angelo. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 15:9(2024), pp. 1-16. [10.1038/s41419-024-07096-5]
Cozzi, Marta; Magri, Stefania; Tedesco, Barbara; Patelli, Guglielmo; Ferrari, Veronica; Casarotto, Elena; Chierichetti, Marta; Pramaggiore, Paola; Cor...espandi
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