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SUMMARY:The Roles of the Epilepsy-Associated Kinase CDKL5 - Dr Sila Ultani
 r\, Francis Crick Institute\, London
DTSTART:20250127T123000Z
DTEND:20250127T133000Z
UID:TALK226024@talks.cam.ac.uk
CONTACT:Kate Davenport
DESCRIPTION:CDKL5 is an X-linked serine/threonine kinase predominantly exp
 ressed in the mammalian brain. Loss-of-function mutations in CDKL5 lead to
  CDKL5 Deficiency Disorder (CDD)\, a rare neurodevelopmental disease chara
 cterized by early-onset seizures\, profound developmental impairments and 
 a lifelong need for care. To investigate CDKL5’s role in brain developme
 nt\, we utilized chemical genetic and proteomics approaches to identify it
 s substrates in the mouse brain. This research uncovered several physiolog
 ical substrates\, including microtubule-binding proteins (EB2\, MAP1S\, an
 d ARHGEF2) and the voltage-gated calcium channel Cav2.3.\nTo explore the f
 unctional significance of these phosphorylations\, we developed phosphomut
 ant mouse models for MAP1S and Cav2.3. Our findings indicate that MAP1S ph
 osphorylation influences microtubule binding\, stabilizes dendritic microt
 ubules\, regulates tubulin tyrosination\, and supports dynein-mediated tra
 nsport in neuronal dendrites. Disruptions in these processes lead to impai
 red synapse development and learning deficits. Similarly\, our studies on 
 Cav2.3 reveal that loss of its phosphorylation results in a gain-of-functi
 on effect\, mimicking the impact of ultrarare CACNA1E mutations found in e
 pilepsy patients. These results suggest that inhibiting Cav2.3 activity co
 uld provide therapeutic benefits for CDD. \nWe also discovered that CDKL2 
 phosphorylates several CDKL5 substrates in the brain\, raising the possibi
 lity that enhancing CDKL2 or related kinases could offer a therapeutic str
 ategy for CDD.\n
LOCATION:CRUK CI Lecture Theatre
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