Molecular mechanisms of spectrin-dependent axonal organization and function in cerebellar granule cells

项目总结 βII-SPECTIN是亚膜神经元细胞骨架中普遍存在的一种蛋白。βII- 血影蛋白与F-肌动蛋白和骨架蛋白结合，组成离子通道、膜转运蛋白和肌动蛋白的复杂网络. 细胞黏附分子。βII-SPECTIN还促进细胞器和囊泡的双向运输。我们的实验室 最近有报道称，SPTBN1变异是一种发育迟缓综合征的遗传原因 与智力残疾、自闭症谱系障碍、多动症和癫痫并存。然而，神经元类型 和最容易受到βII-幽灵蛋白功能缺陷影响的大脑回路及其对多样性的具体贡献 神经系统的表现还没有完全阐明。我的初步研究表明，βII-SPECTIN 小脑功能在调节小脑功能中的重要作用及小脑功能障碍可能参与SPTBN1 综合症。为了开始揭示βII-幽灵蛋白在小脑中的作用，我将重点研究它的功能 通过确定βII-幽灵蛋白如何促进小脑颗粒细胞：1)兴奋性轴突的组织 2)轴突细胞器动力学。

PROJECT SUMMARY βII-spectrin (encoded by SPTBN1), is a ubiquitous component of the submembrane neuronal cytoskeleton. βII- spectrin binds F-actin and ankyrins to organize complex networks of ion channels, membrane transporters and cell adhesion molecules. βII-spectrin also promotes bidirectional transport of organelles and vesicles. Our lab recently reported de novo SPTBN1 variants as the genetic cause of a developmental delay syndrome that is comorbid with intellectual disability, autism spectrum disorder, ADHD, and seizures. However, the neuron types and brain circuits most vulnerable to deficits in βII-spectrin function and their specific contribution to the diverse neurological presentations are not fully elucidated. My preliminary studies indicate that βII-spectrin plays important roles in modulating cerebellar function and that cerebellar dysfunction may contribute to the SPTBN1 syndrome. To begin to unravel the roles of βII-spectrin in the cerebellum, I will focus on investigating its function in cerebellar granule cells by determining how βII-spectrin promotes: 1) the organization of excitable axonal domains and 2) axonal organelle dynamics.