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

TDP-43 蛋白病对阿尔茨海默病和相关痴呆哺乳动物模型中逆转录转座子激活和细胞类型特异性脆弱性的影响

• 批准号: 10560868
• 负责人: ROGER B SHER
• 金额: $ 51.88万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560868
• 关键词: ALS pathology; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyotrophic Lateral Sclerosis; Anti-Retroviral Agents; Astrocytes; Automobile Driving; Autopsy; Biochemistry; Bioinformatics; Biological Assay; Biology; Brain; Brain region; Cells; Cellular Assay; Central Nervous System; Cytoplasm; DNA Damage; DNA Markers; DNA Repair; Dementia; Development; Disease; Disease Progression; Distal; Drosophila genus; Elements; Endogenous Retroviruses; Event; Frontotemporal Dementia; Functional disorder; Gene Expression Profile; Genome; Glial Fibrillary Acidic Protein; Human; Inflammation; Injections; L1 Elements; Measures; Mediating; Microglia; Modeling; Molecular; Motor; Motor Cortex; Motor Neurons; Mus; Mutant Strains Mice; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurons; Nuclear; Nuclear Protein; Oligodendroglia; Pathologic; Pathology; Pathway interactions; Patients; Proteins; Reporter; Research Personnel; Retrotransposon; Retroviridae; Reverse Transcriptase Inhibitors; Role; Signal Pathway; Signal Transduction; Site; Source; Spinal; Stavudine; System; Testing; Tissues; Toxic effect; Transgenic Mice; Translational Research; Vertebral column; Virus; cell type; derepression; disease phenotype; frontotemporal lobar dementia amyotrophic lateral sclerosis; motor disorder; mouse model; neuroblastoma cell; neurotoxic; novel; overexpression; promoter; protein TDP-43; protein aggregation; transcriptome sequencing

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.

项目摘要： 这项提议将测试TDP-43蛋白病变和内源性的关键方面的作用 逆转录病毒在肌萎缩侧索硬化症/额颞叶痴呆的病理中的作用 阿尔茨海默氏症和相关痴呆症。这一提议将在哺乳动物模型中检验这一假说 反转录转座子(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细胞RTE的激活，(2) TDP-43对RTE的作用是非细胞自主的，并且(3)RTES参与毒性和 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来研究 TDP-43-Q331K在已建立的神经变性/痴呆模型中的作用 突变小鼠。两种互补的方法将被用来研究TDP-43在 反转录转座子生物学。首先，TG-hTDP-43-Q331K低表达，但不是低表达 TG-hTPD43-WT模型发展为运动功能障碍和脊髓运动神经元丢失。第二, AAV脑内TDP-43在神经元和星形胶质细胞中的高表达 注射提供了研究神经元和神经元之间非细胞自主信号的手段 神经胶质细胞。通过用AAV病毒驱动神经元或神经胶质细胞的过度表达，TDP-43的作用 病理上RTE的表达也将被确定，并且非细胞的自主传播 这些细胞类型之间的毒性作用。最后，可溶性齐聚反应与反应体系之间的关系 疾病表型将被确定，允许追求更多的翻译 逆转录酶抑制剂和解聚酶的潜在用途研究 用于减轻或延缓疾病进展的化合物。