Abstract
The kinase TTBK1 is predominantly expressed in the central nervous system and has been implicated in neurodegenerative diseases including Alzheimer’s disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis through its ability to phosphorylate the proteins tau and TDP-43. Mutations in the closely related gene TTBK2 cause spinocerebellar ataxia, type 11. However, it remains unknown whether altered TTBK1 activity alone can drive neurodegeneration. In order to characterize the consequences of neuronal TTBK1 upregulation in adult brains, we have generated a transgenic mouse model with inducible pan-neuronal expression of human TTBK1. We find that these inducible TTBK1 transgenic mice (iTTBK1 Tg) exhibit motor and cognitive phenotypes, including decreased grip strength, hyperactivity, limb-clasping, and spatial memory impairment. These behavioral phenotypes occur in conjunction with progressive weight loss, neuroinflammation, and severe cerebellar degeneration with Purkinje neuron loss. Phenotype onset begins weeks after TTBK1 induction, culminating in average mortality around 7 weeks post induction. The iTTBK1 Tg animals lack any obvious accumulation of pathological tau or TDP-43, indicating that TTBK1 expression drives neurodegeneration in the absence of detectable pathological protein deposition. In exploring TTBK1 functions, we identified the autophagy related protein GABARAP to be a novel interacting partner of TTBK1 and show that GABARAP protein levels increase in the brain following induction of TTBK1. These iTTBK1 Tg mice exhibit phenotypes reminiscent of spinocerebellar ataxia, and represent a new model of cerebellar neurodegeneration.
Highlights
Spinocerebellar ataxias (SCAs), a heterogeneous group of neurodegenerative movement disorders, affect an estimated 2.7 per 100,000 individuals worldwide [19]
Young adult transgenic mice were removed from DOX exposure to induce iTTBK1 transgene expression and 1 month later brains were assessed by immunohistochemistry for increased TTBK1 immunoreactivity
We have developed a novel model of inducible human TTBK1 overexpression in the murine central nervous system
Summary
Spinocerebellar ataxias (SCAs), a heterogeneous group of neurodegenerative movement disorders, affect an estimated 2.7 per 100,000 individuals worldwide [19]. Mutations in the gene encoding tau tubulin kinase-2, TTBK2, cause spinocerebellar ataxia, type 11 (SCA11) These mutations act in a dominant negative manner, and conditional knockout of mouse Ttbk recapitulates phenotypes of SCA11 including loss of motor coordination and cerebellar degeneration [2,3,4, 7, 8]. SCA11 exhibits nearly complete loss of Purkinje cells and significant loss of cerebellar granule cells, accompanied by tau-positive neurofibrillary tangles, neuropil threads, and neurites in the hippocampus, substantia nigra, and other brain regions [8]. Another tau tubulin kinase, TTBK1, has been implicated in neurodegenerative disease. Co-expression of human TTBK1 with P301L mutant tau increases tau pathology including phosphorylation and aggregation, and drives locomotor dysfunction and loss of motor neurons in the spinal cord [29]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
