Chantelle F. Sephton, Ph.D.
CERVO Brain research centre
Investigation of new therapeutic targets to slow or prevent the development of severe neurodegenerative diseases
Dr. Chantelle Sephton's research program aims to find new therapeutic targets to slow or stop the development of devastating diseases such as amyotrophic lateral sclerosis and frontotemporal dementia. Dr. Sephton is particularly interested in the role of two proteins, named TDP-43 and FUS, that bind to RNA, the genetic material that is used to produce proteins. These RNA binding proteins play a crucial role in controlling the production of other proteins that are essential for the proper functioning of neurons.
Dr. Sephton's research aims to understand the role of FUS and TDP-43 in regulating the protein production required for the formation of connections between neurons. The loss of connections, or synapses, is a central event in the development of neurodegenerative diseases.
A better understanding of the mechanisms of production and maintenance of healthy synapses and neurons will identify intervention targets that could slow the loss of function associated with neurodegenerative diseases.
The incidence of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD) is growing in the aging population. From the time of diagnosis, the life expectancy is usually between two to 10 years. We have no cure or effective therapies for these diseases, because we do not understand the underlying disease mechanisms by which they occur. The loss of synapses is predicted to be an early event in the disease process and it occurs prior to neurodegeneration. Despite this fact, there have been few systematic studies that examine how synapse loss occurs or how disease-associated proteins contribute to loss of synaptic communication. RNA binding proteins are essential for maintaining synaptic homeostasis. My research program examines how the RNA-binding proteins, TDP-43 and FUS, regulate the production of essential proteins important for healthy neuron function. We are examining this using our novel mouse and neuron culture models employing biochemistry and imaging techniques. Our goal is to drive the field towards a better understanding of RNA regulation and its role in maintaining healthy neurons. The overreaching goal of my research is to search and identify better drug targets for the development of drugs to slow or prevent neurodegeneration. Finding better therapeutics will impact both the individuals who suffer from these diseases and their families.
Myriam Sévigny, M.Sc.
Mari Carmen Pelaez, MSc-PHD student
Yousri Benchaar-Master's student
Jasmine Bélanger-Master's student
Pelaez, M.C*., Desmeules A.*, Gelon P.A.*, Glasson B.*, Marcadet L.*, Rodgers A.*, Phaneuf D., Pozzi S., Dutchak P.A., Julien J, Sephton C.F. Neuronal dysfunction caused by FUSR521G promotes ALS-associated phenotypes that are attenuated by NF-B inhibition. Resubmitted to Acta Neuropath. Comm. Aug 2023
Aggarwal G., Banerjee S., Jones S.A., Pavlack M., Benchaar Y.*, Bélanger J.*, Sévigny M.*, Smith D.M., Niehoff M.L., de Vera I.M., Petkau T.L., Leavitt B.R., Ling K., Jafar-Nejad P., Rigo F., Morley J.E., Farr S.A., Dutchak P.A., Sephton C.F., Nguyen A.D. (2022). Antisense oligonucleotide-based therapeutic strategy for progranulin-deficient frontotemporal dementia. Submitted to the Journal of Biological Chemistry. Biorxiv: https://www.biorxiv.org/content/10.1101/2022.01.12.476053v3.full
Nicolas G., Sévigny M*., Lecoquierre F., Marguet F., Deschênes A., Peláez M.C.*, Feuillette S., Audebrand A., Lecourtois M., Rousseau S., Richard A., Cassinari K., Deranmecourt V., Dyckaerts C., Bonland A., Deleuze J., Echavarria J.C., Gelp E., Akiyama H., Kawakami I., Wong T.H., Van Rooij J., Van Swieten J.C., Campion D., Dutchak P.A., Wallon D., Lavoie-Cardinal F., Laquerrière A., Lecrux-Rovelet A., Sephton C.F. (2022). A postzygotic de novo NCDN mutation identified in a sporadic FTLD patient results in Neurochondrin haploinsufficiency and altered FUS granule dynamics. Acta Neuropathologica Communications. 10(1): 20
Gelon P.A.*, Dutchak P.A., Sephton, C.F. (2022). Synaptic dysfunction in ALS and FTD: anatomical and molecular changes provide insights into mechanisms of disease. Frontiers in Molecular Neuroscience. 15:1000183
Hui J.B., Hernandez J.C., Pelaez M.C.*, Sévigny M.*, Venkatasubrmani J.P., Proulx C.D., Sephton C.F., Dutchak P.A. (2022). NPRL2 inhibition of mTORC1 controls sodium channel-dependent action potentials and brain amino acid homeostasis. eNeuro. 9(2): 0317-21
Sévigny, M., Bourdeau Julien I., Venkatasubrmani J.P., Hui, J.B., Dutchak P.A, Sephton C.F. FUS contributes to mTOR-dependent inhibition of translation. Journal of Biological Chemistry. (2020) 295 (52), 18459-18473. https://www.jbc.org/content/295/52/18459.full.pdf
Bourdeau Julien I., Sephton C.F. and Dutchak P.A., Metabolic Networks Influencing Skeletal Muscle Fiber Composition (2018) Frontiers in Cell and Developmental Biology. 6(125). Cited: 10. https://www.frontiersin.org/articles/10.3389/fcell.2018.00125/full
Sephton C.F. and Yu G. The Function of RNA Binding Proteins at the Synapse: Implications for Neurodegeneration. (2015) Cellular and Molecular Life Sciences. (2015) 72(19): 3621-3635. https://link.springer.com/content/pdf/10.1007/s00018-015-1943-x.pdf
Sephton C.F., Tang A., Brooks M., West J., Kulkarni A., Stubblefield J., Liu Y., Zhang M.Q., Green C.B., Huber K.M., Huang E.J., Herz J., Yu G., Activity-Dependent FUS Dysregulation Disrupts Synaptic Homeostasis at Dendritic Spines. (2014) Proceedings of the National Academy of Sciences. 111(44): E4769-78. https://www.pnas.org/content/pnas/111/44/E4769.full.pdf
Sephton C.F., Cenik, C., Kucukural A., Dammer E.B., Cenik B., Han Y., Dewey C.M., Roth F.P., Herz J., Peng J., Moore M.J., Yu G Identification of Neuronal RNA Targets of TDP-43-Containing Ribonucleoprotein Complexes. (2011) Journal of Biological Chemistry. 286 (2): 1204-15. https://www.jbc.org/action/showPdf?pii=S0021-9258%2820%2956309-6
Sephton C.F., Good S.K., Atkin S., Dewey C.M., Mayer P., Herz J., Yu, G. TDP-43 is a Developmentally-Regulated Protein Essential for Early Embryonic Development. (2010) Journal of Biological Chemistry. 285 (49): 6826-34. https://www.jbc.org/action/showPdf?pii=S0021-9258%2819%2937847-0
Bachelor of Science (B.Sc.): University of Saskatchewan, Department of Biochemistry
Doctorate of Philosophy (Ph.D.): University of Saskatchewan, Department of Psychiatry
Post-doctoral Fellow: University of Texas Southwestern Medical Center at Dallas
Faculty (Instructor, non-tenure): University of Texas Southwestern Medical Center at Dallas
2601 Chemin de la Canardière