Host: Greg Findlay

Venue: Small Lecture Theatre, Medical Sciences Institute, SLS

Abstract:

CDKL5 is an X-linked serine/threonine kinase highly expressed in the mammalian brain. Loss-of- function mutations in CDKL5 cause a rare neurodevelopmental disorder named CDKL5 Deficiency Disorder (CDD). Patients with CDD have early-onset seizures, severe neurodevelopmental deficits and they require life-long care. To determine the roles of CDKL5 in brain development, we aimed to identify CDKL5’s substrates in the brain using chemical genetic and proteomics approaches. Our work revealed multiple physiological substrates of CDKL5 in the brain including microtubule binding proteins EB2, MAP1S and ARHGEF2 and the voltage-gated calcium channel, Cav2.3.

We generated phosphomutant mouse models for MAP1S and Cav2.3 to study the roles of these phosphorylations in mouse brain. We find that MAP1S phosphorylation affects its microtubule binding, dendritic microtubule stability, tubulin tyrosination and dynein-mediated transport on neuronal dendrites leading to defective synapse development and learning. In addition, our work in Cav2.3 shows that the loss of Cav2.3 phosphorylation leads to gain of function of the channel, similar to the functional effects of the ultrarare CACNA1E mutations in epilepsy patients. We postulate that inhibition of Cav2.3 can be beneficial for CDD. More recently, we revealed that CDKL2 phosphorylates multiple CDKL5 substrates in brain, thus upregulation of CDKLs can be a therapeutic avenue.

Bio:

Sila Ultanir is a Senior Group Leader at the Francis Crick Institute, London, UK. Sila completed her undergraduate education in Bilkent University, Turkey. She did her PhD on neuroscience, focusing on dendrite development and synaptogenesis in Dr Rafael Yuste's lab at Columbia University, New York. She then moved to Dr Anirvan Ghosh's laboratory at the University of California, San Diego, where she studied the role of NMDA receptors on dendritic spine development. Sila then joined Dr Yuh-Nung Jan's laboratory at University of California, San Francisco and worked on kinase signaling mechanisms on dendrite development in collaboration with Dr Kevan Shokat's laboratory. She started her lab at NIMR, Mill Hill, London in 2013.

Hosts: Esther Sammler and Dario Alessi

Venue: MSI Small Lecture Theatre, SLS

Abstract:

Parkinson’s disease is one of the most frequent neurodegenerative diseases. While the root cause and molecular mechanisms underlying Parkinson’s disease remain incompletely understood, lysosomal dysfunction is critically disturbed, which contributes to the accumulation of proteins and defective mitochondria. Our lab is specialized in the study of endolysosomal polyamine transporters, such as ATP13A2 (PARK9), which has been genetically linked with Parkinson’s disease. Our research revealed that ATP13A2 transports polyamines out of the lysosome, contributing to lysosomal and mitochondrial health. Our work in the Aligning Science Across Parkinson’s program demonstrated that a disturbed polyamine homeostasis affects Parkinson’s disease symptoms and that polyamines modulate Parkinson’s disease pathways. Furthermore, our molecular insights into the regulation of ATP13A2 have offered new therapeutic opportunities for Parkinson’s disease, which we actively pursue. Finally, we have also characterized the closely related polyamine transporters ATP13A3 and ATP13A4, which we propose as new drug targets for cancer.

Bio:

Positions

2012-present: Group Leader of the Laboratory of Cellular Transport System, KU Leuven, Belgium 

2020-present: Professor at the Faculty of Medicine, KU Leuven, Belgium

2018-2020: Associate Professor at the Faculty of Medicine, KU Leuven, Belgium

2011-2018: Assistant Professor – Tenure Track at the Faculty of Medicine, KU Leuven, Belgium

Awards

2018: Ernest-Solvay Award for Neurosciences (25,000 €)

2020: Achievement Award Valine de Spoelberch - Queen Elisabeth Medical Foundation of Neurosciences (100,000 €)

Selected References

1. ATP13A2 deficiency disrupts lysosomal polyamine export. van Veen S, Martin S, Van den Haute C, Benoy V, Lyons J, Vanhoutte R, Kahler JP, Decuypere JP, Gelders G, Lambie E, Zielich J, Swinnen JV, Annaert W, Agostinis P, Ghesquière B, Verhelst S, Baekelandt V, Eggermont J, Vangheluwe P. Nature. 2020 Jan 29, 578, 419–424. doi: 10.1038/s41586-020-1968-7. (IF 43.07)        
2. ATP13A2-mediated endo-lysosomal polyamine export counters mitochondrial oxidative stress. Vrijsen S, Besora-Casals L, van Veen S, Zielich J, Van den Haute C, Hamouda NN, Fischer C, Ghesquière B, Tournev I, Agostinis P, Baekelandt V, Eggermont J, Lambie E, Martin S, Vangheluwe P. Proc Natl Acad Sci U S A. 2020 Dec 8;117(49):31198-31207. doi: 10.1073/pnas.1922342117.
3. The polyamine transporter ATP13A3 mediates DFMO-induced polyamine uptake in neuroblastoma. Mujahid Azfar, Weiman Gao, Chris Van den Haute, Lin Xiao, Mawar Karsa, Ruby Pandher, Emma Ronca, Angelika Bongers, Ayu Karsa, Dayna Spurling, Xinyi Guo, Chelsea Mayoh, Mark R. Burns, Steven H.L. Verhelst, Murray D. Norris, Michelle Haber, Peter Vangheluwe, Klaartje Somers. bioRxiv 2024.02.20.581161; doi: https://doi.org/10.1101/2024.02.20.581161
4. ATP13A4 Upregulation Drives the Elevated Polyamine Transport System in the Breast Cancer Cell Line MCF7. van Veen S, Kourti A, Ausloos E, Van Asselberghs J, Van den Haute C, Baekelandt V, Eggermont J, Vangheluwe P. Biomolecules. 2023 May 31;13(6):918. doi: 10.3390/biom13060918.
5. ATP13A3 Variants Promote Pulmonary Arterial Hypertension by Disrupting Polyamine Transport. Bin Liu, Mujahid Azfar, Ekaterina Legchenko, James A. West, Shaun Martin, Chris Van den Haute, Veerle Baekelandt, John Wharton, Luke Howard, Martin R. Wilkins, Peter Vangheluwe, Nicholas W. Morrell, Paul D. Upton. bioRxiv 2023.08.29.554603; doi: https://doi.org/10.1101/2023.08.29.554603