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Loss of siRNA based gene silencing and retrotransposon activation in TDP-43 mediated neurodegeneration

TDP-43 介导的神经变性中基于 siRNA 的基因沉默和逆转录转座子激活的丧失

基本信息

批准号：
9001385
负责人：
JOSHUA T DUBNAU
金额：
$ 32.23万
依托单位：
COLD SPRING HARBOR LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9001385
关键词：
Age Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Antibodies Apoptosis Beryllium Biogenesis Biological Assay Biological Markers Brain Cell Death Clinical Cytoplasmic Inclusion Data Disease Disease model Drosophila genome Drosophila genus Exhibits Frontotemporal Lobar Degenerations Gene Silencing Genetic Genome Gypsies Human Human Genome Inherited Integrase Inhibitors Literature Locomotion Longevity Mammals Mediating Methods Modeling Monitor Nerve Degeneration Neurodegenerative Disorders Neurons Organism Pathology Patients Play Proteins Publications RNA RNA Interference RNA-Binding Proteins RNA-Directed DNA Polymerase Regulation Repetitive Sequence Reporter Retrotransposon Reverse Transcriptase Polymerase Chain Reaction Role Small Interfering RNA Small RNA Testing Therapeutic Intervention Toxic effect Transcript Virus age related base chromosomal location genetic manipulation in vivo innovation loss of function neurodegenerative phenotype neurogenesis neurotoxic neurotoxicity normal aging protein TDP-43 public health relevance research study response transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): The TDP-43 protein plays a role in a broad suite of neurodegenerative disorders including Frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis, and potentially, Alzheimer's disease. TDP-43 is a multifunctional protein with many known cellular roles. So, while the importance of TDP-43 in neurodegeneration is established, the mechanisms of TDP-43 toxicity are unclear. We have discovered a new role for TDP-43 in regulating small-RNA based gene silencing, which is critical to block expression of retrotransposons. Retrotransposons are virus-like sequences that are encoded in our genomes and are capable of replicating and inserting at new chromosomal positions. The toxic potential of transposons in the germline is established. So our discovery provides a plausible hypothesis for toxic effects of TDP-43 in neurons. Our preliminary studies provide strong evidence that TDP-43 normally helps to silence transposons and that this function is disrupted both in FTLD patients and a Drosophila disease model. Our proposed experiments will use genetic manipulations in Drosophila to test three key specific hypotheses: 1) that TDP-43 pathology disrupts argonaute-2 mediated silencing; 2) that TDP-43 pathology activates retrotransposons in Drosophila brain; 3) that Retrotransposon activation contributes to neurodegeneration

描述（由申请人提供）：TDP-43蛋白在一系列广泛的神经退行性疾病中起作用，包括额颞叶变性（FTLD）、肌萎缩侧索硬化症和潜在的阿尔茨海默病。TDP-43是一种多功能蛋白，具有许多已知的细胞作用。因此，虽然TDP-43在神经变性中的重要性已经确立，但TDP-43毒性的机制尚不清楚。我们已经发现TDP-43在调节基于小RNA的基因沉默中的新作用，这对于阻断逆转录转座子的表达至关重要。逆转录转座子是在我们的基因组中编码的病毒样序列，能够复制并插入新的染色体位置。转座子在种系中的毒性潜力被确立。因此，我们的发现为TDP-43在神经元中的毒性作用提供了一个合理的假设。我们的初步研究提供了强有力的证据表明，TDP-43通常有助于沉默转座子，并且这种功能在FTLD患者和果蝇疾病模型中都被破坏。我们提出的实验将使用果蝇中的遗传操作来测试三个关键的特定假设：1）TDP-43病理学破坏argonaute-2介导的沉默; 2）TDP-43病理学激活果蝇脑中的逆转录转座子; 3）逆转录转座子激活有助于神经变性