Mattéa J. Finelli
The epilepsy-associated protein TBC1D24 is required for normal development, survival and vesicle trafficking in mammalian neurons
Finelli, Mattéa J.; Aprile, Davide; Castroflorio, Enrico; Jeans, Alexander; Moschetta, Matteo; Chessum, Lauren; Degiacomi, Matteo T.; Grasegger, Julia; Lupien-Meilleur, Alexis; Bassett, Andrew; Rossignol, Elsa; Campeau, Philippe M.; Bowl, Michael R.; Benfenati, Fabio; Fassio, Anna; Oliver, Peter L.
Authors
Davide Aprile
Enrico Castroflorio
Alexander Jeans
Matteo Moschetta
Lauren Chessum
Matteo Degiacomi matteo.t.degiacomi@durham.ac.uk
Part Time Teacher
Julia Grasegger
Alexis Lupien-Meilleur
Andrew Bassett
Elsa Rossignol
Philippe M. Campeau
Michael R. Bowl
Fabio Benfenati
Anna Fassio
Peter L. Oliver
Abstract
Mutations in the Tre2/Bub2/Cdc16 (TBC)1 domain family member 24 (TBC1D24) gene are associated with a range of inherited neurological disorders, from drug-refractory lethal epileptic encephalopathy and DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures) to non-syndromic hearing loss. TBC1D24 has been implicated in neuronal transmission and maturation, although the molecular function of the gene and the cause of the apparently complex disease spectrum remain unclear. Importantly, heterozygous TBC1D24 mutation carriers have also been reported with seizures, suggesting that haploinsufficiency for TBC1D24 is significant clinically. Here we have systematically investigated an allelic series of disease-associated mutations in neurons alongside a new mouse model to investigate the consequences of TBC1D24 haploinsufficiency to mammalian neurodevelopment and synaptic physiology. The cellular studies reveal that disease-causing mutations that disrupt either of the conserved protein domains in TBC1D24 are implicated in neuronal development and survival and are likely acting as loss-of-function alleles. We then further investigated TBC1D24 haploinsufficiency in vivo and demonstrate that TBC1D24 is also crucial for normal presynaptic function: genetic disruption of Tbc1d24 expression in the mouse leads to an impairment of endocytosis and an enlarged endosomal compartment in neurons with a decrease in spontaneous neurotransmission. These data reveal the essential role for TBC1D24 at the mammalian synapse and help to define common synaptic mechanisms that could underlie the varied effects of TBC1D24 mutations in neurological disease.
Citation
Finelli, M. J., Aprile, D., Castroflorio, E., Jeans, A., Moschetta, M., Chessum, L., …Oliver, P. L. (2019). The epilepsy-associated protein TBC1D24 is required for normal development, survival and vesicle trafficking in mammalian neurons. Human Molecular Genetics, 28(4), 584-597. https://doi.org/10.1093/hmg/ddy370
Journal Article Type | Article |
---|---|
Acceptance Date | Oct 9, 2018 |
Online Publication Date | Oct 17, 2018 |
Publication Date | Feb 15, 2019 |
Deposit Date | Dec 4, 2018 |
Publicly Available Date | Dec 4, 2018 |
Journal | Human Molecular Genetics |
Print ISSN | 0964-6906 |
Electronic ISSN | 1460-2083 |
Publisher | Oxford University Press |
Peer Reviewed | Peer Reviewed |
Volume | 28 |
Issue | 4 |
Pages | 584-597 |
DOI | https://doi.org/10.1093/hmg/ddy370 |
Public URL | https://durham-repository.worktribe.com/output/1307823 |
Files
Published Journal Article
(22.5 Mb)
PDF
Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/
Published Journal Article (Advance online version)
(22.5 Mb)
PDF
Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/
Copyright Statement
Advance online version © The Author(s) 2018. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/),
which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
You might also like
Course Materials for an Introduction to Data-Driven Chemistry
(2023)
Journal Article
Denoising Diffusion Probabilistic Models on SO(3) for Rotational Alignment
(2022)
Presentation / Conference Contribution
Identification of Graphene Dispersion Agents through Molecular Fingerprints
(2022)
Journal Article
Allophycocyanin A is a carbon dioxide receptor in the cyanobacterial phycobilisome
(2022)
Journal Article
Downloadable Citations
About Durham Research Online (DRO)
Administrator e-mail: dro.admin@durham.ac.uk
This application uses the following open-source libraries:
SheetJS Community Edition
Apache License Version 2.0 (http://www.apache.org/licenses/)
PDF.js
Apache License Version 2.0 (http://www.apache.org/licenses/)
Font Awesome
SIL OFL 1.1 (http://scripts.sil.org/OFL)
MIT License (http://opensource.org/licenses/mit-license.html)
CC BY 3.0 ( http://creativecommons.org/licenses/by/3.0/)
Powered by Worktribe © 2024
Advanced Search