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

 描述(申请人提供)：TDP-43蛋白在一系列神经退行性疾病中发挥作用，包括额颞叶变性(FTLD)、肌萎缩侧索硬化症，以及潜在的阿尔茨海默病。TDP-43是一种多功能蛋白，具有多种已知的细胞功能。因此，虽然TDP-43在神经退行性变中的重要性已经确定，但TDP-43的毒性机制尚不清楚。我们发现了TDP-43在调节基于小RNA的基因沉默中的一个新角色，这是阻止反转录转座子表达的关键。反转录转座子是在我们的基因组中编码的类似病毒的序列，能够在新的染色体位置复制和插入。转座子在生殖系中的毒性潜力已经确定。因此，我们的发现为TDP-43对神经元的毒性作用提供了一个可信的假说。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，这一功能在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的遗传操作来检验三个关键的特定假设：1)TDP-43的病理破坏ArgAerte-2介导的沉默；2)TDP-43的病理激活果蝇脑中的反转录转座子；3)反转录转座子的激活有助于神经退化

 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