Primary cilia are vital signaling organelles that extend from most types of cells, including neurons and glia. These structures are essential for the 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 Ttbk2 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 Ttbk2 conditional mutant mice quickly lose cilia throughout the brain. We show that conditional knockout of the key ciliary trafficking gene Ift88 in adult mice results in nearly identical cerebellar phenotypes to those of the Ttbk2 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.

中文翻译：

---

TTBK2和原发性纤毛对于小脑浦肯野神经元的连通性和存活至关重要

初级纤毛是重要的信号细胞器，它从大多数类型的细胞（包括神经元和神经胶质细胞）延伸。这些结构对于许多组织和器官的发育必不可少，但是，它们在成年组织，尤其是大脑神经元中的功能仍然未知。Tau微管蛋白激酶2（TTBK2）是纤毛形成的关键调节因子，在遗传性神经退行性疾病11型小脑共济失调（SCA11）中也发生突变。在这里，我们显示成年小鼠中Ttbk2的条件性基因敲除会导致变性小脑表型，概括了SCA11的各个方面，包括运动协调缺陷和浦肯野细胞（PC）完整性的缺陷。我们还发现Ttbk2有条件的突变小鼠迅速失去整个大脑的纤毛。我们显示成年小鼠中的关键睫毛运输基因Ift88的条件敲除导致小脑表型与Ttbk2敲除的小脑表型几乎相同，表明纤毛信号的破坏是这些表型的关键驱动力。我们的数据表明，初级纤毛在维持成人小脑中PC的功能中起着不可或缺的作用，并揭示了有关神经退行性病变机制的新颖见解。