TDP-43 Proteinopathies in ALS-Dementia

泛素阳性包涵体在肌萎缩侧索硬化症(ALS)和额颞叶变性(FTLD)中被发现，前者是一种典型的运动神经元疾病，后者是仅次于阿尔茨海默病的第二常见痴呆症患者。最近，宾夕法尼亚大学(宾夕法尼亚大学)的研究人员确定TDP-43是在这两种疾病中普遍存在的疾病蛋白。由于在ALS和FTLD中发现运动神经元疾病和痴呆，而且由于相同的疾病蛋白在两种疾病中积累，这表明ALS和FTLD代表了神经退行性综合征的相同临床病理谱。因此，该计划项目拨款(PPG)的主要目标是开发一个强有力的研究计划，专注于阐明ALS(分别称为ALS、ALS-Cog和ALS-FTLD)中TDP-43蛋白病变的病因和发病机制，并将它们与有和不有ALS的FTLD进行比较。这一新PPG的研究人员是由宾夕法尼亚大学医生和基础科学家组成的紧密联系和高度整合的多学科小组，他们组成了一个富有成效的合作联盟，并在宾夕法尼亚大学建立了非常全面的临床和基础科学研究计划，以研究患者、人类死后组织和模型系统中的ALS、ALS-Cog和ALS-FTLD。这些研究人员为ALS和FTLD研究提出了一套大胆的目标，将通过4个核心和3个项目来实施。具体地说，他们将：1)招募ALS、ALS-Cog和ALS-FTLD患者；2)开发新的算法来表征ALS患者的认知障碍和痴呆；3)检验在动作动词的表征中语言和运动系统之间存在紧密联系的假设；4)进一步描述ALS、ALS-Cog和ALS-FTLD脑中TDP-43的神经病理谱，并将它们与有ALS和没有ALS的FTLD进行比较；5)确定在病理性TDP-43蛋白病变中产生C-末端片段的过度磷酸化残基和N-末端切割位点，并确定它们在TDP-43蛋白病变机制中的意义；6)建立TDP-43的细胞培养和转基因小鼠模型；7)利用这些模型阐明TDP-43神经退行性变的发病机制；8)确定ALS、ALS-Cog和ALS-FTLD患者中发现的TDP-43基因突变是否是疾病风险因素或致病突变；这些研究和其他研究将有助于更好地理解ALS的认知障碍和痴呆，并为这些疾病的诊断和治疗提供见解。

Ubiquitin positive inclusions are found in amyotrophic lateral sclerosis (ALS), a prototypic motor neuron disease and frontotemporal lobar degeneration (FTLD), the second most common dementia after Alzheimer's disease in patients <65. Recently, investigators at the University of Pennsylvania (PENN) identified TDP-43 as the disease protein ubiquitinated in both disorders. Since motor neuron disease and dementia are found in ALS and FTLD, and since the same disease protein accumulates in both disease entities, this suggests that ALS and FTLD represent the same clinicopathological spectrum of a neurodegenerative syndrome. Thus, the major goals of this Program Project Grant (PPG) is to develop a vigorous research program focused on elucidating the etiology and pathogenesis of TDP-43 proteinopathies in ALS without or with cognitive impairment or dementia (designated as ALS, ALS-Cog and ALS-FTLD, respectively) and compare them to FTLD with and without ALS. The investigators of this new PPG are a close-knit and highly integrated multidisciplinary group of PENN physicians and basic scientists who have formed a productive collaborative alliance and established a very comprehensive clinical and basic science research program at PENN to study ALS, ALS-Cog and ALS-FTLD in patients, in human postmortem tissues and in model systems. These investigators propose a set of bold objectives for ALS and FTLD research that will be implemented through 4 Cores and 3 Projects. Specifically, they will: 1) recruit ALS, ALS-Cog and ALS-FTLD patients; 2) develop new algorithms to characterize the cognitive impairments and dementia in ALS patients; 3) test the hypothesis that there is a tight link between language and motor systems in the representation of action verbs; 4) further characterize the spectrum of TDP-43 neuropathologies in ALS, ALS-Cog and ALS-FTLD brains and compare them with FTLD with and without ALS; 5) identify hyperphosphorylated residues and N-terminal cleavage sites that generate C-terminal fragments in pathological TDP-43 and determine their significance in mechanisms of TDP-43 proteinopathies; 6) establish cell culture and transgenic mouse models of TDP-43; 7) use these models to elucidate the pathogenic mechanisms of neurodegeneration in TDP-43; 8) determine if genetic variants in TDP-43 found in patients with ALS, ALS-Cog and ALS-FTLD are disease risk factors or pathogenic disease causing mutations; These and other studies will lead to improved understanding of the cognitive impairments and dementia in ALS as well as provide insights on the diagnosis and treatment of these disorders.