Altered molecular and cellular mechanisms in KIF5A-associated neurodegenerative or neurodevelopmental disorders.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
27 Sep 2024
27 Sep 2024
Historique:
received:
28
02
2024
accepted:
19
09
2024
revised:
17
09
2024
medline:
28
9
2024
pubmed:
28
9
2024
entrez:
27
9
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39333504
doi: 10.1038/s41419-024-07096-5
pii: 10.1038/s41419-024-07096-5
doi:
Substances chimiques
Kinesins
EC 3.6.4.4
KIF5A protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
692Subventions
Organisme : Fondazione Telethon (Telethon Foundation)
ID : GGP19128
Organisme : AFM-Téléthon (French Muscular Dystrophy Association)
ID : 23236
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)
ID : PRIN n. 2022EFLFL8
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)
ID : PRIN n. P2022B5J32
Organisme : European Molecular Biology Organization (EMBO)
ID : Scientific Exchange Grant n. 9643
Organisme : Fondazione Cariplo (Cariplo Foundation)
ID : 2021-1544
Organisme : Fondazione Cariplo (Cariplo Foundation)
ID : 2021-1544
Organisme : Ministero della Salute (Ministry of Health, Italy)
ID : RF-2018-12367768
Organisme : Ministero della Salute (Ministry of Health, Italy)
ID : RRC 2023
Informations de copyright
© 2024. The Author(s).
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