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

Bowie, Emily; Goetz, Sarah C.

doi:10.1101/689448

Cited by 16 publications

(29 citation statements)

References 66 publications

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“…Upon serum starvation, removal of CP110 from the mother centriole is a key step in the initiation of cilia formation (8). Tau tubulin kinase 2 (TTBK2), a protein mutated in the inherited movement disorder, Spinocerebellar ataxia type 11, promotes the removal of CP110 and recruitment of IFT proteins to build the ciliary axoneme (8)(9)(10). TTBK2 is recruited selectively to the mother centriole by binding to CEP164 (11,12).…”

Section: > Introductionmentioning

confidence: 99%

Pathogenic LRRK2 regulates ciliation probability upstream of Tau Tubulin kinase 2

Sobu

Wawro

Dhekne

et al. 2020

Preprint

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Mutations that activate LRRK2 protein kinase cause Parkinson's disease. We have shown previously that Rab10 phosphorylation by LRRK2 enhances its binding to RILPL1 and together, these proteins block cilia formation in a variety of cell types including patient derived iPS cells. We have used live cell fluorescence microscopy to identify, more precisely, the effect of LRRK2 kinase activity on both the formation of cilia triggered by serum starvation and loss of cilia seen upon serum re-addition. LRRK2 activity decreases the overall probability of ciliation without changing the rates of cilia formation in R1441C LRRK2 MEF cells. Cilia loss in these cells is accompanied by ciliary decapitation. Kinase activity does not change the timing or frequency of decapitation or the rate of cilia loss, but increases the percent of cilia that are lost upon serum addition. LRRK2 activity, or overexpression of RILPL1 protein, blocks release of CP110 from the mother centriole, a step normally required for early ciliogenesis. In both cases, failure of CP110 uncapping was due to failure to recruit TTBK2, a kinase needed for CP110 release. In contrast, recruitment of EHD1, another step important for ciliogenesis, appears unaltered. These experiments provide critical detail to our understanding of the cellular consequences of pathogenic LRRK2 mutation, and indicate that LRRK2 blocks ciliogenesis upstream of TTBK2 and enhances the deciliation process in response to serum addition.KEY WORDS: LRRK2, Rab GTPase, primary cilia, Parkinson's disease SIGNIFICANCE STATEMENTMutations that activate LRRK2 protein kinase cause Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases, in particular Rab8 and Rab10. Phosphorylated Rabs bind preferentially to a distinct set of effectors and block in primary ciliation in multiple cell types. We show here that the cilia blockade is upstream of the recruitment of TTBK2 kinase to the mother centriole, a step required for the release of CP110 and subsequent cilia formation. This study provides fundamental information related to how pathogenic LRRK2 interferes with normal cell physiology.

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Section: > Introductionmentioning

confidence: 99%

Pathogenic LRRK2 regulates ciliation probability upstream of Tau Tubulin kinase 2

Sobu

Wawro

Dhekne

et al. 2020

Preprint

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“…Neuronal cilia have been implicated in a variety of developmental processes including dendritic branching and axon targeting [5,11,13,33]. Despite these studies, relatively little is known about the functions of cilia on mature neurons.…”

Section: Discussionmentioning

confidence: 99%

“…In both mouse lines for this study, Cre-mediated Ift88 excision occurs after neuronal differentiation. Removal of cilia from other neuronal strains, or in adult animals, has not produced noticeable changes in neuron survival up until at least 6 months of age [7,27,32,33].…”

Section: Validation Of Cilia Lossmentioning

confidence: 99%

Neuron-specific cilia loss alters locomotor responses to amphetamine

Ramos

Roberts

Jasso

et al. 2020

Preprint

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The neural mechanisms that underlie responses to drugs of abuse are complex, and impacted by a number of neuromodulatory peptides. Within the past ten years it has been discovered that several of the receptors for neuromodulators are enriched in the primary cilia of neurons.Primary cilia are microtubule-based organelles that project from the surface of nearly all mammalian cells, including neurons. Despite what we know about cilia, our understanding of how cilia regulate neuronal function and behavior is still limited. The primary objective of this study was to investigate the contributions of primary cilia on specific neuronal populations to behavioral responses to amphetamine. To test the consequences of cilia loss on amphetamineinduced locomotor activity we selectively ablated cilia from dopaminergic or GAD2-GABAergic neurons in mice. Cilia loss had no effect on baseline locomotion in either mouse strain. Both female and male mice lacking cilia on dopaminergic neurons showed significantly reduced responses to acute administration of 3.0 mg/kg amphetamine compared to wildtype mice. In contrast, changes in the locomotor response to amphetamine in mice lacking cilia on GAD2-GABAergic neurons were primarily driven by reductions in locomotor activity in males. Following repeated amphetamine administration (1.0 mg/kg/day over 5 days), mice lacking cilia on GAD2-GABAergic neurons exhibited enhanced sensitization of the locomotor stimulant response to the drug, whereas mice lacking cilia on dopaminergic neurons did not differ from their wildtype controls. These results indicate that cilia play neuron-specific roles in both acute and neuroplastic responses to psychostimulant drugs of abuse.

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“…These structures are required to transduce and integrate signaling through a variety of important developmental pathways, with dysfunction of primary cilia linked to several recessive genetic syndromes. In addition to their roles in embryonic development, cilia also persist on the cells of most tissues during adulthood (1)(2)(3)(4).…”

Section: Introductionmentioning

confidence: 99%

“…This implies that TTBK2 acts in a pathway that is critical for the regulation of ciliogenesis. TTBK2 is important for maintaining the stability of the ciliary axoneme (9), and both of these requirements for this kinase are linked to a role for TTBK2 in a human neurodegenerative disease (4).…”

Section: Introductionmentioning

confidence: 99%

A complex of distal appendage-associated kinases linked to human disease regulates ciliary trafficking and stability

Loukil

Barrington

Goetz

2020

Preprint

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Cilia biogenesis is a complex, multi-step process involving the coordination of multiple cellular trafficking pathways. Despite the importance of ciliogenesis in mediating the cellular response to cues from the microenvironment, we have only a limited understanding of the regulation of cilium assembly. We previously identified a kinase that acts as a key regulator of ciliogenesis, TTBK2. In the course of efforts to identify additional players in the TTBK2 pathway, we identified the CK2 subunit CSNK2A1. Super-resolution microscopy revealed that CSNK2A1 is a centrosomal protein predominantly concentrated at the mother centriole and associated with the distal appendages. CSNK2A1 and TTBK2 interact both physically and functionally: Csnk2a1 knockout in Ttbk2 hypomorphic cells partially corrects defects in cilia formation and length. In addition, Csnk2a1 mutant cilia are longer than those of control cells and exhibit instability, particularly at the tip. Csnk2a1 mutant cilia also abnormally accumulate key cilia assembly and SHH-related proteins including IFT, GLI2, KIF7, and Smoothened (SMO). De novo mutations of Csnk2a1 were recently linked to the human genetic disorder Okur-Chung neurodevelopmental syndrome (OCNDS). Consistent with the role of CSNK2A1 in cilium stability, we find that expression of OCNDS-associated Csnk2a1 variants in wild-type cells caused ciliary structural defects. Our findings provide new insights on mechanisms involved in ciliary length regulation, trafficking, and stability that in turn shed light on the significance and implications of cilia instability in human disease.

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

Cited by 16 publications

References 66 publications

Pathogenic LRRK2 regulates ciliation probability upstream of Tau Tubulin kinase 2

Pathogenic LRRK2 regulates ciliation probability upstream of Tau Tubulin kinase 2

Neuron-specific cilia loss alters locomotor responses to amphetamine

A complex of distal appendage-associated kinases linked to human disease regulates ciliary trafficking and stability

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