TBC1d23调节细胞器互作及突变引起脑桥小脑发育不全的机制研究

脑桥小脑发育不全（Pontocerebellar hypoplasia， PCH）是一组涉及神经发育障碍的常染色体隐性遗传疾病。TBC1D23是新发现的与PCH发作相关的基因，但其分子机制却不清楚。TBC1D23位于高尔基体，介导高尔基体-内体囊泡的互作。我们前期研究表明突变TBC1D23的关键氨基酸会导致高尔基体-内体囊泡的互作紊乱，进而引起斑马鱼脑部发育异常。本项目针对细胞器互作的生理病理功能，拟利用哺乳动物细胞系、斑马鱼模型，结合体外生化实验，以高尔基体-内体囊泡互作为主线，研究TBC1D23在该互作中的作用及调节内体-高尔基体物质转运的机制，TBC1D23突变导致的脑桥小脑发育不全分子机制。该研究将揭示细胞器互作在内体-高尔基体运输中作用与调节机制，为脑桥小脑发育不全病的诊断与治疗提供重要理论依据。

Pontocerebellar hypoplasia (PCH) is a neurological disorder that affect the development of the brain，in particularly the pons and cerebellum. Homozygous mutations of TBC1D23 have been found recently to lead to PCH; however, the underlying molecular mechanisms remain unclear. In cells, TBC1D23 is localized on trans-Golgi network (TGN), and directly mediates the TGN-endosomal vesicles contacts. The applicant’s laboratory studies the molecular mechanism of intracellular transport and related diseases. In preliminary studies, we found that mutation of key residues of TBC1D23 disrupt the contacts between TGN and endosomal vesicles. The same mutants caused abnormal neuronal growth and brain development in zebrafish, thus indicating that defects in TGN-endosomal vesicles contacts are, at least partially, responsible for the pathogenesis of TBC1D23-related PCH. In the funded program, we will further investigate the molecular mechanism by which TBC1D23 regulates endosome-to-TGN transport via mediating organelle-vesicle contacts, and dissect the connection between TBC1D23 mutations with PCH, using a combination of cellular, biochemical, and zebrafish studies. We studies could provide new insights into functions of organelle contacts in vesicular trafficking, and reveal new mechanisms into the pathophysiology of PCH