TDP-43 Proteinopathies in ALS-Dementia

在肌萎缩侧索硬化症（ALS）（一种原型运动神经元疾病）和额颞叶变性（FTLD）（在<65岁的患者中仅次于阿尔茨海默病的第二种最常见的痴呆）中发现了泛素阳性包涵体。最近，宾夕法尼亚大学（PENN）的研究人员将TDP-43确定为这两种疾病中泛素化的疾病蛋白。由于在ALS和FTLD中发现了运动神经元疾病和痴呆，并且由于相同的疾病蛋白在两种疾病实体中积累，这表明ALS和FTLD代表神经退行性综合征的相同临床病理学谱。因此，该计划项目补助金（PPG）的主要目标是制定一项强有力的研究计划，重点是阐明ALS中TDP-43蛋白病的病因和发病机制，无论是否伴有认知障碍或痴呆（分别称为ALS，ALS-Cog和ALS-FTLD），并将其与FTLD进行比较。这个新PPG的研究人员是一个紧密联系和高度整合的多学科小组，由宾夕法尼亚州的医生和基础科学家组成，他们已经形成了一个富有成效的合作联盟，并在宾夕法尼亚州建立了一个非常全面的临床和基础科学研究计划，以研究ALS，ALS-Cog和ALS-FTLD在患者中，在人类死后组织和模型系统中。这些研究人员为ALS和FTLD研究提出了一系列大胆的目标，这些目标将通过4个核心和3个项目来实现。具体而言，它们将：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）测试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）进一步表征ALS、ALS-Cog和ALS-FTLD脑中TDP-43神经病理学的谱，并将它们与有和无ALS的FTLD进行比较; 5）鉴定病理性TDP-43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神经变性的致病机制; 8）确定ALS、ALS-Cog和ALS-FTLD患者中发现的TDP-43遗传变异是否是疾病风险因素或致病性疾病突变;这些和其他研究将有助于提高对ALS中认知障碍和痴呆的理解，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.