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： 该提案将测试TDP-43蛋白质病和内源性角色的关键方面 肌萎缩性侧索硬化症/额颞痴呆和 阿尔茨海默氏症和相关痴呆症。该建议将在哺乳动物模型中检验该假设 逆转座子（RTE）的重新激活是神经退行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的RTE激活，（2） TDP-43对RTE的影响是非单元自主的，（3）RTE有助于毒性和 非电池自治。该建议还将建立有史以来第一个调查的哺乳动物平台 TDP-43和RTE在已建立的神经变性/痴呆模型中，TDP-43-Q331K 突变小鼠。将使用两种完整的方法来研究TDP-43在 逆转录盆地生物学。首先，低表达的TG-HTDP-43-Q331K，但不是低表达的 TG-HTPD43-WT模型，发展运动功能障碍和脊柱运动神经元的丧失。第二， 通过局部AAV脑在神经元或星形胶质细胞中TDP-43的高过表达 注射提供了研究神经元之间非细胞自主信号传导的手段 神经胶质。通过仅在具有AAV病毒的神经元或神经胶质中驱动过度表达，TDP-43的作用 还将确定RTE表达的病理学，并将 这些细胞类型之间的有毒作用。最后，固体寡聚与 将确定疾病表型，从而追求其他翻译 研究逆转录酶抑制剂和分解酶的潜在使用 减轻或延迟疾病进展的化合物。