TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A

Brown, A-L; Wilkins, OG; Keuss, MJ; Hill, SE; Zanovello, M; Lee, WC; Bampton, A; Lee, FCY; Masino, L; Qi, YA; Bryce-Smith, S; Gatt, A; Hallegger, M; Fagegaltier, D; Phatnani, H; Newcombe, J; Gustavsson, EK; Seddighi, S; Reyes, JF; Coon, SL; Ramos, D; Schiavo, G; Fisher, EMC; Raj, T; Secrier, M

Neuroscience & Neuroimaging Research Collection

Journal article

TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A

Abstract:: TAR DNA-binding protein 43 (TDP-43) TDP-43 is an RNA-binding protein whose cytosolic aggregation and nuclear depletion is linked to amyotrophic lateral sclerosis (ALS), fronto-temporal dementia (FTD), and found in 60% of Alzheimer's cases. TDP-43 controls RNA functions like splicing and stability. In disease, TDP-43 dysfunction causes cryptic splicing, where intronic sequences are incorporated into mature RNA. Though cryptic splicing signifies TDP-43 dysfunction post-mortem, the full extent of TDP-43’s cryptic splicing targets, and how these cryptic splicing events affect disease progression is unknown. This thesis performed a comprehensive analysis of TDP-43 regulated cryptic events in neuronal cell lines and in human post-mortem tissue, as well as providing the first ever transcriptome wide study of RNA stability after TDP-43 depletion in human neurons. I created reproducible analysis pipelines to perform splicing analyses and used these pipelines to uncover thousands of TDP-43 regulated cryptic splicing events in human neuronal cell lines. Furthermore, I revealed a profound RNA destabilising effect of TDP-43 depletion using the metabolic labelling technique SLAM- sequencing. Through analysis of the largest RNA-sequencing database of ALS/FTD tissue, the New York Genome Consortium ALS/FTD dataset, I revealed potential TDP-43 disease effectors and biomarkers of TDP-43 proteinopathy. Finally, I played a role in discovering the molecular mechanisms underlying the ALS/FTD risk SNPs in the UNC13A gene

Publication status:: Published

Peer review status:: Peer reviewed

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APA Style

Brown, A.-L., Wilkins, O. G., Keuss, M. J., Hill, S. E., Zanovello, M., Lee, W. C., Bampton, A., Lee, F. C. Y., Masino, L., Qi, Y. A., Bryce-Smith, S., Gatt, A., Hallegger, M., Fagegaltier, D., Phatnani, H., Newcombe, J., Gustavsson, E. K., Seddighi, S., Reyes, J. F., … Secrier, M. (2022). TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A. Nature, 603(7899), 131–137.

MLA Style

Brown, A-L, et al. “TDP-43 Loss and ALS-Risk SNPs Drive Mis-Splicing and Depletion of UNC13A.” Nature, vol. 603, no. 7899, 2022, pp. 131–37.

Chicago Style

Brown, A-L, OG Wilkins, MJ Keuss, et al. 2022. “TDP-43 Loss and ALS-Risk SNPs Drive Mis-Splicing and Depletion of UNC13A.” Nature 603 (7899): 131–37.
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