Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, S182, 1660 South Columbian Way, Seattle, WA, 98108, USA.
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, 98195, USA.
Mol Neurodegener. 2018 Feb 6;13(1):7. doi: 10.1186/s13024-018-0237-9.
Progressive neuron loss in the frontal and temporal lobes of the cerebral cortex typifies frontotemporal lobar degeneration (FTLD). FTLD sub types are classified on the basis of neuronal aggregated protein deposits, typically containing either aberrantly phosphorylated TDP-43 or tau. Our recent work demonstrated that tau tubulin kinases 1 and 2 (TTBK1/2) robustly phosphorylate TDP-43 and co-localize with phosphorylated TDP-43 in human postmortem neurons from FTLD patients. Both TTBK1 and TTBK2 were initially identified as tau kinases and TTBK1 has been shown to phosphorylate tau epitopes commonly observed in Alzheimer's disease and other tauopathies.
To further elucidate how TTBK1/2 activity contributes to both TDP-43 and tau phosphorylation in the context of the neurodegeneration seen in FTLD, we examined the consequences of elevated human TTBK1/2 kinase expression in transgenic animal models of disease.
We show that C. elegans co-expressing tau/TTBK1 tau/TTBK2, or TDP-43/TTBK1 transgenes in combination exhibit synergistic exacerbation of behavioral abnormalities and increased pathological protein phosphorylation. We also show that C. elegans co-expressing tau/TTBK1 or tau/TTBK2 transgenes in combination exhibit aberrant neuronal architecture and neuron loss. Surprisingly, the TTBK2/TDP-43 transgenic combination showed no exacerbation of TDP-43 proteinopathy related phenotypes. Additionally, we observed elevated TTBK1/2 protein expression in cortical and hippocampal neurons of FTLD-tau and FTLD-TDP cases relative to normal controls.
Our findings suggest a possible etiology for the two most common FTLD subtypes through a kinase activation driven mechanism of neurodegeneration.
大脑皮质额颞叶的进行性神经元丧失是额颞叶变性（FTLD）的特征。FTLD 亚型是基于神经元聚集蛋白沉积物分类的，通常包含异常磷酸化的 TDP-43 或 tau。我们最近的工作表明，tau 微管激酶 1 和 2（TTBK1/2）可强烈磷酸化 TDP-43，并与 FTLD 患者死后神经元中的磷酸化 TDP-43 共定位。TTBK1 和 TTBK2 最初均被鉴定为 tau 激酶，并且 TTBK1 已被证明可磷酸化在阿尔茨海默病和其他 tau 病中常见的 tau 表位。
为了进一步阐明 TTBK1/2 活性如何在 FTLD 中所见的神经退行性变背景下促进 TDP-43 和 tau 磷酸化，我们检查了升高的人类 TTBK1/2 激酶表达在疾病转基因动物模型中的后果。
我们显示，共表达 tau/TTBK1、tau/TTBK2 或 TDP-43/TTBK1 转基因的秀丽隐杆线虫表现出协同性行为异常加剧和病理性蛋白磷酸化增加。我们还显示，共表达 tau/TTBK1 或 tau/TTBK2 转基因的秀丽隐杆线虫表现出异常的神经元结构和神经元丢失。令人惊讶的是，TTBK2/TDP-43 转基因组合未加剧与 TDP-43 蛋白病相关表型。此外，我们观察到 FTLD-tau 和 FTLD-TDP 病例的皮质和海马神经元中 TTBK1/2 蛋白表达升高。
我们的发现通过神经退行性变的激酶激活驱动机制为两种最常见的 FTLD 亚型提供了一种可能的病因。
