TDP-43 Proteinopathies in ALS-Dementia

泛素阳性包涵体见于肌萎缩性侧索硬化症（ALS），这是一种典型的运动神经元疾病和额颞叶变性（FTLD），是65岁以下患者中仅次于阿尔茨海默病的第二大常见痴呆。最近，宾夕法尼亚大学（PENN）的研究人员发现TDP-43是两种疾病中泛素化的疾病蛋白。由于运动神经元疾病和痴呆在ALS和FTLD中都有发现，并且在这两种疾病实体中积累了相同的疾病蛋白，这表明ALS和FTLD代表了相同的神经退行性综合征的临床病理谱。因此，该计划项目拨款（PPG）的主要目标是制定一个强有力的研究计划，重点阐明没有或伴有认知障碍或痴呆的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，并将其与伴有和不伴有ALS的FTLD进行比较。这个新PPG的研究人员是一个紧密结合、高度整合的多学科小组，由宾夕法尼亚大学的医生和基础科学家组成，他们形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一个非常全面的临床和基础科学研究项目，研究ALS、ALS- cog和ALS- ftld在患者、人类死后组织和模型系统中的作用。这些研究人员为ALS和FTLD研究提出了一系列大胆的目标，将通过4个核心和3个项目来实施。具体而言，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)验证动作动词表征中语言与运动系统之间存在紧密联系的假设；4)进一步表征ALS、ALS- cog和ALS-FTLD脑TDP-43神经病理谱，并与合并和未合并ALS的FTLD进行比较；5)鉴定病理性TDP-43中产生c端片段的过磷酸化残基和n端裂解位点，并确定其在TDP-43蛋白发病机制中的意义；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)确定在ALS、ALS- cog和ALS- ftld患者中发现的TDP-43基因变异是否为疾病危险因素或致病突变；这些和其他研究将有助于提高对ALS患者认知障碍和痴呆的认识，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.