Role of Retrotransposon Activity in Neurodegeneration and Alzheimer's Disease

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PROJECT SUMMARY (OVERALL) Retrotransposable elements (RTEs) comprise ~45% of the human genome. Known as ‘mobile DNA’ they can insert into new genomic locations using a 'copy and paste' mechanism. This process, retrotransposition, can be deleterious at multiple levels, and has largely been viewed as molecular parasitism. Not surprisingly, host organ- isms have evolved multiple silencing mechanisms to protect their genomes. This competitive and adversarial relationship between RTEs and their hosts is evident in the evolutionary record of genome sequences. This record is silent on the activity of RTEs in somatic tissues, since this information is not passed from one generation to another, and RTEs were thought to be largely silent in somatic cells. However, in the past 10-15 years evi- dence started emerging that somatic RTE activity is more frequent than anticipated, with members of this PPG contributing important early evidence. Five years ago, this debate culminated in the submission of this PPG, founded on the hypothesis that the somatic activation of RTEs represents a novel and hitherto unappreciated molecular aging process. Our research program was designed to test this hypothesis and elucidate the underly- ing mechanisms. The next five years saw a validation of this hypothesis, not just by our team, but also many other groups. It is now apparent that with aging, multiple host defense mechanisms become compromised, and repetitive sequences in general, not just active RTEs, increase their expression. As to the underlying mecha- nisms by which this somatic onslaught 'can hurt us' we were in for a surprise: we discovered that RTEs dere- pressed during aging, in particular LINE-1 (L1) elements, can generate cytoplasmically localized cDNA reverse transcripts. These cDNAs are potent activators of a Type-I Interferon (IFN-I) response, which in turn stimulates the innate immune system. We believe this leads to a phenomenon known as 'sterile inflammation' or 'inflam- maging', a known hallmark of aging that has been implicated in a variety of age-related diseases. In a nutshell, the host organism perceives RTE activation as an invading virus and mounts an appropriate anti-viral response – unfortunately, given that the invader is embedded in our genomes, this response is futile and ultimately coun- terproductive. Interestingly, the central nervous system (CNS) appears to be a 'privileged site' for RTE activity, with relatively high levels of expression and ease of further upregulation. Multiple lines of evidence indicate that RTE activation is associated with pathology, and in particular neuroinflammation. Neurodegenerative diseases, and in particular dementias such as Alzheimer's Disease (AD), are among the most devastating and feared diseases of aging. The goal of this PPG will be to explore in detail the newly discovered somatic L1 lifecycles in neuronal and non-neuronal cells of the CNS, the L1 surveillance mechanisms in the CNS, how they fail, the consequences of that failure, and ultimately, how we can fix this. We will use human induced pluripotent stem cell (iPSC) models as well as directly reprogrammed neurons, Drosophila and mouse models of AD, and human postmortem tissue. F.H. Gage, a widely-known AD pioneer, joins the original PPG team on this quest.