TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons

ABSTRACT Primary cilia are vital signaling organelles that extend from most types of cells, including neurons and glia. However, their function, particularly on neurons in the adult brain, remains largely unknown. Tau tubulin kinase 2 (TTBK2) is a critical regulator of ciliogenesis, and is also mutated 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 human SCA11 including motor coordination deficits, loss of synaptic connections to Purkinje cells (PCs), and eventual loss of PCs. 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, supporting disruption of ciliary signaling as a key driver of these phenotypes. Our data suggest that primary cilia play an integral role in maintaining adult neuronal function, and offers novel insights into the mechanisms involved in neurodegeneration.