Altered molecular and cellular mechanisms in KIF5A-associated neurodegenerative or neurodevelopmental disorders
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.
Authors
- Marta Cozzi (ORCID: https://orcid.org/0000-0001-9428-7054)
- Chiara Pisciotta (ORCID: https://orcid.org/0000-0002-3850-076X)
- Marta Chierichetti (ORCID: https://orcid.org/0000-0003-0549-0742)
- Lorenzo Nanetti (ORCID: https://orcid.org/0000-0002-1952-4539)
- Paola Pramaggiore (ORCID: https://orcid.org/0000-0003-1399-7973)
- Antonia Ratti (ORCID: https://orcid.org/0000-0002-4264-6614)
- P. Rusmini (ORCID: https://orcid.org/0000-0001-9989-0733)
- B. Tedesco (ORCID: https://orcid.org/0000-0002-7077-3696)
- Daniela Di Bella (ORCID: https://orcid.org/0000-0003-0912-5136)
- Davide Pareyson (ORCID: https://orcid.org/0000-0001-6854-765X)
- Caterina Mariotti (ORCID: https://orcid.org/0000-0003-2405-3564)
- V. Crippa (ORCID: https://orcid.org/0000-0002-3058-5711)
- Jessica Mandrioli (ORCID: https://orcid.org/0000-0002-9244-9782)
- Stefania Magri (ORCID: https://orcid.org/0000-0002-9610-7544)
- Viviana Pensato (ORCID: https://orcid.org/0000-0001-9798-2669)
- Angelo Poletti (ORCID: https://orcid.org/0000-0002-8883-0468)
- Veronica Ferrari (ORCID: https://orcid.org/0000-0003-2514-9445)
- Stefano D’Arrigo (ORCID: https://orcid.org/0000-0001-5188-9418)
- Riccardo Cristofani (ORCID: https://orcid.org/0000-0003-2719-846X)
- M. Galbiati (ORCID: https://orcid.org/0000-0003-3250-5591)
- Elena Casarotto (ORCID: https://orcid.org/0000-0002-3842-8243)
- Elisa Sarto (ORCID: https://orcid.org/0000-0002-0699-956X)
- Margherita Piccolella (ORCID: https://orcid.org/0000-0002-5130-1116)
- Cinzia Gellera (ORCID: https://orcid.org/0000-0002-3582-665X)
- Franco Taroni (ORCID: https://orcid.org/0000-0002-2420-5233)
- Laura Cornaggia
- Guglielmo Patelli
Institutions
- University of Modena and Reggio Emilia (IT)
- University of Milan (IT)
- Azienda Ospedaliero-Universitaria di Modena (IT)
- IRCCS Istituto Auxologico Italiano (IT)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2024-09-27
- DOI
- https://doi.org/10.1038/s41419-024-07096-5
- Citations
- 14
- Primary Topic
- Hereditary Neurological Disorders
- Type
- article
- Field-Weighted Citation Impact
- 3.76
Funders
- University College London