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

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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.