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.

中文翻译：

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成人发病的泛神经元人 tau 微管蛋白激酶 1 表达导致小鼠严重的小脑神经变性

激酶 TTBK1 主要在中枢神经系统中表达，并通过其磷酸化蛋白质 tau 和 TDP-43 的能力与神经退行性疾病有关，包括阿尔茨海默病、额颞叶变性和肌萎缩侧索硬化。密切相关的基因 TTBK2 中的突变会导致脊髓小脑性共济失调，11 型。然而，单独改变 TTBK1 活性是否可以驱动神经变性仍然未知。为了表征成人大脑中神经元 TTBK1 上调的后果，我们生成了具有人类 TTBK1 可诱导泛神经元表达的转基因小鼠模型。我们发现这些可诱导的 TTBK1 转基因小鼠 (iTTBK1 Tg) 表现出运动和认知表型，包括握力下降、多动、肢体紧握和空间记忆障碍。这些行为表型与进行性体重减轻、神经炎症和严重的小脑变性伴浦肯野神经元丢失同时发生。表型开始于 TTBK1 诱导后数周，在诱导后 7 周左右达到平均死亡率。iTTBK1 Tg 动物没有任何明显的病理性 tau 或 TDP-43 积累，表明 TTBK1 表达在没有可检测的病理性蛋白质沉积的情况下驱动神经变性。在探索 TTBK1 功能时，我们确定自噬相关蛋白 GABARAP 是 TTBK1 的新型相互作用伙伴，并表明 TTBK1 诱导后脑中 GABARAP 蛋白水平增加。这些 iTTBK1 Tg 小鼠表现出让人联想到脊髓小脑共济失调的表型，并代表了一种新的小脑神经变性模型。