Mar 21: Neuronal Development & CDKL5-related Disorders

Title : Neuronal Development & CDKL5-related Disorders

Speaker:Zhiqi Xiong.

Host: Prof. Xiaotao Li

When: 2013-03-21    14:00

Where: Conference Room 534, School of Life Sciences

Abstract：The X-link gene cyclin-dependent kinase-like 5 (CDKL5) is mutated in patients with severe neurodevelopmental disorders including an early-onset variant of Rett syndrome. The expression of CDKL5 is developmentally regulated and enriched in the brain. Our recent studies have shown that CDKL5 plays important roles in neuronal development such as neurite growth and dendritic spine morphogenesis. Polarized protein trafficking is fundamental to neuronal development and function. Palmitoylation, a reversible lipid modification, has emerged as an important mechanism for regulating this process. Palmitoylated proteins are sorted in the secretory pathways and trafficked to specific compartments. Although no evidence exists, it is possible that in secretory organelles some non-palmitoylated proteins may achieve polarized trafficking by association with palmitoylated proteins. The postsynaptic scaffolding protein PSD-95 is a major palmitoylated protein in neurons and its synaptic targeting depends on palmitoylation4. We find that PSD-95 interacts with CDKL5, a protein whose mutations cause severe neurodevelopmental disorders, in a palmitoylation-dependent fashion and regulates its targeting to excitatory synapses. Interestingly, certain disease-associated mutations which abolish this interaction reduce synaptic localization of CDKL5. Moreover, disruption of this interaction diminishes synaptic targeting of CDKL5 and inhibits dendritic spine growth. Thus, our findings reveal an unexpected role of palmitoylated PSD-95 in synaptic targeting of CDKL5, which may represent a novel mechanism for protein trafficking. These results may also provide insights into the pathogenesis of CDKL5-related disorders.