Altered reverse transcriptase-dependent gene diversification mechanisms in Alzheimer's disease

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PROJECT SUMMARY/ABSTRACT Somatic gene recombination (SGR) may increase gene copy number and diversity of disease-relevant genes that contribute to age-related neurodegeneration. The proposed SGR mechanism requires gene transcription, reverse transcription of RNA by an endogenous reverse transcriptase (RT), and DNA strand breaks at sites that enable retro-insertion. However, detailed studies on endogenous reverse transcriptase activity in the normal and diseased human brain is virtually unknown. Furthermore, the identity and possible diversity of endogenous reverse transcriptase genes in the human brain has yet to be defined. A strong candidate is the long interspersed nuclear element, LINE1 (L1), that was long thought to be a dead evolutionary remnant of ancient RNA viruses. There are hundreds of thousands of LINE1 sequences in our human genomes and some are clearly active. Based upon sequence data, each LINE1 element contains a potentially active or activatable endogenous reverse transcriptase gene that encodes a likely RT protein, ORF2p, with reverse transcriptase and endonuclease activities. LINE1 is a known mediator of global chromosomal instability, genomic instability, and genetic heterogeneity and has been implicated in the progression of cancer, aging, and multiple neurodegenerative diseases. Candidate Juliet Nicodemus’ project and training program will fall within the parental R01’s Aim 3, and we added additional granularity for this supplement as part of her focused pursuit of Aim 3, as well as to enable optimal training experiences. She will pursue the central hypothesis that diverse forms of functional reverse transcriptases differ in the normal and AD human brain.