Regulation mechanism and functional genomics of LINE1 RNA in TDP-43 linked neurodegeneration

RNA代谢功能障碍在多种神经退行性疾病中起关键作用，包括阿尔茨海默病（AD）和阿尔茨海默病相关性痴呆（ADRD），如额颞叶痴呆（FTD）。这些疾病的一个病理学标志是RNA结合蛋白（RBP）TAR DNA结合蛋白-43（TDP-43）的核清除和胞质聚集，在20-60%的AD患者和50%的FTD患者中发现。TDP-43在mRNA加工中具有多种功能。它也参与调节反转录转座子激活，但分子机制尚未解决。 逆转录转座子元件是移动的遗传元件，其通过转录成RNA、逆转录成DNA然后插入基因组中的新位点来复制自身，该过程称为逆转录转座。长散布核元件-1（LINE 1）是目前人类中唯一活跃的、自主的反转录转座子家族，约占人类基因组的20%。只有一小部分LINE 1被认为是移动的。由于截短、重排和点突变，大多数是无活性的。LINE 1 RNA在染色质状态调控中的“非编码RNA”功能越来越受到关注。 在本研究项目中，我们将破译LINE 1 RNA失调的分子机制，特别是TDP-43功能丧失导致的LINE 1 RNA衰变途径功能障碍，这与阿尔茨海默病和阿尔茨海默病相关痴呆的病理学有关。我们将确定LINE 1 RNA升高与染色质可及性、组蛋白修饰和转录基因网络破坏的因果关系。我们将结合联合收割机人诱导多能干细胞分化的神经元和AD和FTD患者的死后组织来剖析与TDP-43蛋白病相关的分子机制。我们提出的研究将提供更深层次的机制了解AD/ADRD及其在功能基因组学中的作用，这在很大程度上是在过去的研究不足。这些发现将有助于理解疾病机制，促进阿尔茨海默病和阿尔茨海默病相关痴呆症的治疗发展。

Dysfunction of RNA metabolism has emerged to play crucial roles in multiple neurodegeneration diseases, including Alzheimer’s Disease (AD) and Alzheimer’s Disease related dementias (ADRD), such as frontal temporal dementia (FTD). One pathologic hallmark of these diseases is the nuclear clearance and cytosolic aggregation of the RNA binding protein (RBP) TAR DNA binding protein-43 (TDP-43), which is found in 20-60% AD patients and 50% FTD patients. TDP-43 has multiple functions in mRNA processing. It is also implicated in regulating retrotransposon activation, but the molecular mechanism is not resolved. Retrotransposon elements are mobile genetic elements that copy themselves by transcribing into RNA, reverse-transcribed into DNA and then inserted into new sites in the genome, a process known as retrotransposition. Long interspersed nuclear element-1 (LINE1) is the only currently active, autonomous family of retrotransposon elements in human, and accounts for ~20% of the human genome. Only a small subset of LINE1s are thought to be mobile. The majority are inactive due to truncations, rearrangements and point mutations. There are increasing interest in understanding the “noncoding RNA” functions of LINE1 RNA in chromatin state regulation. In this research project, we will decipher the molecular mechanism of LINE1 RNA dysregulation, particularly the dysfunction of LINE1 RNA decay pathway caused by TDP-43 loss of function, which is associated with the pathology of Alzheimer’s Disease and Alzheimer’s Disease Related Dementias. We will determine the causal relationship of LINE1 RNA elevation with chromatin accessibility, histone modification and transcriptional gene network disruption. We will combine human induced pluripotent stem cell-differentiated neurons and postmortem tissues from AD and FTD patients to dissect the molecular mechanisms associated with TDP-43 proteiopathy. Our proposed study will provide deeper mechanistic understanding of the retroelement dysregulation in AD/ADRD and its role in functional genomics, which is largely understudied in the past. The findings will help understanding disease mechanisms and facilitating therapy development for Alzheimer’s Disease and Alzheimer’s Disease Related Dementias.