University Program in Genetics and Genomics, Duke University, Durham, United States.
Department of Pharmacology and Cancer Biology, Duke University, Durham, United States.
Elife. 2020 Jan 14;9:e51166. doi: 10.7554/eLife.51166.
Primary cilia are vital signaling organelles that extend from most types of cells, including neurons and glia. These structures are essential for development of many tissues and organs; however, their function in adult tissues, particularly neurons in the brain, remains largely unknown. Tau tubulin kinase 2 (TTBK2) is a critical regulator of ciliogenesis, and is also mutated in a hereditary neurodegenerative disorder, spinocerebellar ataxia type 11 (SCA11). Here, we show that conditional knockout of in adult mice results in degenerative cerebellar phenotypes that recapitulate aspects of SCA11 including motor coordination deficits and defects to Purkinje cell (PC) integrity. We also find that the conditional mutant mice quickly lose cilia throughout the brain. We show that conditional knockout of the key ciliary trafficking gene in adult mice results in nearly identical cerebellar phenotypes to those of the knockout, indicating that disruption of ciliary signaling is a key driver of these phenotypes. Our data suggest that primary cilia play an integral role in maintaining the function of PCs in the adult cerebellum and reveal novel insights into mechanisms involved in neurodegeneration.
初级纤毛是从大多数类型的细胞（包括神经元和神经胶质细胞）延伸出来的重要信号细胞器。这些结构对于许多组织和器官的发育至关重要；然而，它们在成年组织中的功能，特别是大脑中的神经元，仍然很大程度上未知。微管相关蛋白 tau 激酶 2（TTBK2）是纤毛发生的关键调节因子，也在遗传性神经退行性疾病脊髓小脑性共济失调 11 型（SCA11）中发生突变。在这里，我们表明在成年小鼠中条件性敲除 导致退行性小脑表型， recapitulate 包括运动协调缺陷和浦肯野细胞（PC）完整性缺陷在内的 SCA11 的某些方面。我们还发现， 条件性突变小鼠迅速失去整个大脑中的纤毛。我们表明，在成年小鼠中条件性敲除关键纤毛运输基因 几乎与 敲除产生完全相同的小脑表型，表明纤毛信号的中断是这些表型的关键驱动因素。我们的数据表明，初级纤毛在维持成年小脑 PC 功能方面发挥着重要作用，并揭示了神经退行性变相关机制的新见解。
