Project ID CM-HD2024_35


Co Supervisor 1A Institute of Psychiatry, Psychology & Neuroscience, School of Neuroscience, Department of Basic & Clinical NeuroscienceWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Basic & Medical Biosciences, Randall Centre for Cell & Molecular BiophysicsWebsite

Diet-based intervention for the control of epilepsy associated with neurodevelopmental and neurodegerative disorders.

Mutations in EPG5 cause Vici Syndrome, a neurodevelopmental disease associated with subsequent neurodegeneration. EPG5 encodes for a protein that regulates autophagy, by controlling the fusion between autophagosomes and lysosomes. Autophagy is an essential housekeeping mechanism that controls neuronal health.

Our recent work on more than 100 patients and on relevant animal models has evidenced how milder EPG5 variants are involved in a wider variety of neurological syndromes. A frequent co-morbidity of EPG5-associated disorders is epilepsy.
Our work in animal models currently submitted for publication (Autophagy KAUP-2023-0003, please ask for preprint) has suggested that the epilepsy phenotype in EPG5 deficiency is associated with the primary function of EPG5 in controlling the autophagy flux and that it thus can be rescued by caloric restriction, which enhances autophagy.

In this project the student will pursue the following aims
1) To gather detailed information on the clinical aspects of epilepsy in our patient cohort
2) To search wider genomic databases of neurodevelopmental and neurodegenerative disorders (including those associated with epilepsy and movement disorders) for variants of interest in EPG5 and in other relevant autophagy modulators (e.g. WDR45, SNX14, RAB7, SNAP29).
3) To attempt a diet-based approach using caloric restriction and special diets (ketogenic) in available EPG5 animal models (Drosophila and mouse)

These aims will be developed according top the time frame below.
Year 1. Aim 1 alongside Drosophila experiments for Aim 3.
Year 2. Aim 2: Search of genomic databases start of mouse experiments for Aim 3.
Year 3. End of mouse experiments for Aim 3. Thesis write up.

The expected outcome of this translational project is a novel approach for epilepsy prevention and management in patients with EPG5-associated disorders.

This approach would be also easily applicable by extension to many other neurodegenerative diseases with a primary defect in autophagy and that display epilepsy as a co-morbidity.

Representative Publications

1) D.Mazaud, B.Kottler, C.Gonçalves-Pimentel, S.Proelss, N.Tüchler, C.Deneubourg, Y.Yuasa, C.Diebold, H.Jungbluth, E.C.Lai, F.Hirth. A.Giangrande and M.Fanto (2019). Transcriptional regulation of the Glutamate/GABA/Glutamine cycle in adult glia controls motor activity and seizures in Drosophila. J. Neurosci. 39;5269-5283. 2)O.Baron, A.Boudi, C.Dias, M.Schilling, A.Nölle, G.Viczcay-Barrena, I.Rattray, H.Jungbluth, W.Scheper, R.Fleck, G.P.Bates and M.Fanto (2017). Stall in canonical autophagy-lysosome pathways prompts nucleophagy-based nuclear breakdown in neurodegeneration. Curr. Biol. 27;3626-3642. 3)N.Panjwani, A.Shakeshaft, D.Roshandel, F.Lin, A.Collingwood, A.Hall, K.Keenan, C.Deneubourg, F.Mirabella, S.Topp2, BIOJUME Consortium, H.Jungbluth, M.P.Richardson, A.Pastore, M.Fanto, D.K.Pal and L.J. Strug (2022). SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy. Medrxiv.
1)Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Cullup T, Kho AL, Dionisi-Vici C, Brandmeier B, Smith F, Urry Z, Simpson MA, Yau S, Bertini E, McClelland V, Al-Owain M, Koelker S, Koerner C, Hoffmann GF, Wijburg FA, ten Hoedt AE, Rogers RC, Manchester D, Miyata R, Hayashi M, Said E, Soler D, Kroisel PM, Windpassinger C, Filloux FM, Al-Kaabi S, Hertecant J, Del Campo M, Buk S, Bodi I, Goebel HH, Sewry CA, Abbs S, Mohammed S, Josifova D, Gautel M, Jungbluth H. Nat Genet. 2013 Jan;45(1):83-7. doi: 10.1038/ng.2497. 2) EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy. Byrne S, Jansen L, U-King-Im JM, Siddiqui A, Lidov HG, Bodi I, Smith L, Mein R, Cullup T, Dionisi-Vici C, Al-Gazali L, Al-Owain M, Bruwer Z, Al Thihli K, El-Garhy R, Flanigan KM, Manickam K, Zmuda E, Banks W, Gershoni-Baruch R, Mandel H, Dagan E, Raas-Rothschild A, Barash H, Filloux F, Creel D, Harris M, Hamosh A, Kölker S, Ebrahimi-Fakhari D, Hoffmann GF, Manchester D, Boyer PJ, Manzur AY, Lourenco CM, Pilz DT, Kamath A, Prabhakar P, Rao VK, Rogers RC, Ryan MM, Brown NJ, McLean CA, Said E, Schara U, Stein A, Sewry C, Travan L, Wijburg FA, Zenker M, Mohammed S, Fanto M, Gautel M, Jungbluth H. Brain. 2016 Mar;139(Pt 3):765-81. doi: 10.1093/brain/awv393. 3) The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy. Deneubourg C, Ramm M, Smith LJ, Baron O, Singh K, Byrne SC, Duchen MR, Gautel M, Eskelinen EL, Fanto M, Jungbluth H. Autophagy. 2022 Mar;18(3):496-517. doi: 10.1080/15548627.2021.1943177.