Effects of TDP-43 Proteinopathy on Retrotransposon Activation and Cell-Type Specific Vulnerability in a Mammalian Model of Alzheimer's and Related Dementias

项目摘要： 该提案将测试TDP-43蛋白质病和内源性 逆转录病毒在肌萎缩侧索硬化/额颞叶痴呆病理学中的作用， 阿尔茨海默氏症和相关痴呆症。这项提议将在哺乳动物模型中检验这一假设 逆转录转座子（RTEs）的重新激活是神经变性和痴呆的一种手段， 通过以下作用：（1）TDP-43毒性引起神经元和神经胶质中的RTE激活，（2） TDP-43对RTEs的影响是非细胞自主的，（3）RTEs有助于毒性， 非细胞自主性这项提议还将建立一个有史以来第一个哺乳动物平台， TDP- 43和已建立的神经变性/痴呆模型中的RTE，TDP-43-Q331 K 突变小鼠将使用两种互补的方法来研究TDP-43在 反转录转座子生物学首先，低表达的Tg-hTDP-43-Q331 K，但不是低表达的Tg-hTDP-43-Q331 K。 Tg-hTPD 43-WT模型发展运动功能障碍和脊髓运动神经元损失。第二、 TDP-43通过局部AAV脑在神经元或星形胶质细胞中的高过表达 注射提供了研究神经元之间的非细胞自主信号传导的手段， 神经胶质。通过用AAV病毒驱动仅在神经元或神经胶质中的过表达，TDP-43的作用被抑制。 还将确定病理学对RTE表达的影响，并且还将确定RTE表达的非细胞自主扩散。 这些细胞类型之间的毒性作用。最后，可溶性低聚与 疾病表型将被确定，允许追求额外的翻译 逆转录酶抑制剂和解聚酶的潜在用途的研究 用于减轻或延迟疾病进展的化合物。

PROJECT ABSTRACT: This proposal will test key aspects of the roles of TDP-43 proteinopathy and endogenous retroviruses in the pathology of amyotrophic lateral sclerosis/frontotemporal dementia and Alzheimer’s and related dementias. This proposal will test, in a mammalian model, the hypothesis that reactivation of retrotransposons (RTEs) is a means for neurodegeneration and dementia through the following actions: (1) TDP-43 toxicity causes RTE activation in neurons and glia, (2) the effects of TDP-43 on RTEs are non-cell autonomous, and (3) RTEs contribute to toxicity and non-cell autonomy. This proposal will also establish a first-ever mammalian platform to investigate TDP- 43 and RTEs in an established neurodegeneration/dementia model, the TDP-43-Q331K mutant mouse. Two complementary approaches will be used to investigate the role of TDP-43 in retrotransposon biology. First, a low-expressing Tg-hTDP-43-Q331K, but not a low-expressing Tg-hTPD43-WT model, develops motor dysfunction and loss of spinal motor neurons. Second, high overexpression of TDP-43 in either neurons or astrocytes through localized AAV brain injections provides the means to investigate non-cell autonomous signaling between neurons and glia. By driving overexpression only in neurons or glia with AAV virus, the effects of TDP-43 pathology on RTE expression will also be determined, and the non-cell autonomous spread of toxic effects between these cell types. Finally, the relationship of soluble oligomerization to the disease phenotypes will be determined, allowing the pursuit of additional translational investigations into the potential use of reverse transcriptase inhibitors and disaggregase compounds for alleviating or delaying progression of disease.