Abstract
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 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.
Highlights
Primary cilia are organelles that serve as compartments that mediate and integrate essential signaling pathways, including Hedgehog (HH) signaling
We previously showed that Tau tubulin kinase 2 (TTBK2), a kinase causally mutated in the hereditary neurodegenerative disorder spinocerebellar ataxia type 11 (SCA11) (Houlden et al, 2007), is an essential regulator of ciliogenesis (Goetz et al, 2012)
SCA11 is somewhat unusual among SCAs, in part because the reported causal mutations are base pair insertions or deletions within the coding region of TTBK2 (Houlden et al, 2007; Johnson et al, 2008; Lindquist et al, 2017), rather than the expansion of CAG repeats, which is the genetic cause of most SCA subtypes (Hersheson et al, 2012)
Summary
Primary cilia are organelles that serve as compartments that mediate and integrate essential signaling pathways, including Hedgehog (HH) signaling. The primary cilium needs the protein TTBK2 to assemble, and mutations in the gene that codes for this protein cause a neurodegenerative disorder that first appears in adulthood known as spinocerebral ataxia type 11 (SCA11). People with this disease have a movement disorder caused by the loss of neurons called Purkinje cells in the cerebellum. In 2018, researchers showed that mutated versions of TTBK2 associated with SCA11 interfere with the role of normal TTBK2 in assembling the cilium It was unclear whether primary cilia are required for the survival of Purkinje cells in the cerebellum. We provide strong evidence that primary cilia and ciliary signals are important for maintaining connectivity of specific neurons within the brain, and we demonstrate that dysfunction of primary cilia can cause or contribute to neurodegeneration within the mammalian brain
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