The Retrotransposon storm and the dangers of a Collyer's genome

Abstract

Like the famous Collyer's mansion in NY, our genomes have accumulated vast quantities of sequences that have been referred to as 'junk DNA,' much of which consists of retrotransposons (RTEs). A recent literature establishes the phenomenology that many RTEs become expressed at progressively higher levels during the course of normal aging. This seems to reflect gradual loss of heterochromatin in old age. In addition, RTEs appear to be precociously expressed in brains of younger animals that are experiencing neurodegenerative decline. Although it is difficult to distinguish cause from consequence, several recent studies support the contention that RTE expression, and even perhaps transposition, causally contribute to both the normal deterioration seen with age and to the precipitous decline in some neurodegenerative disorders. This may reflect a two hit model in which normal age-dependent loss of heterochromatin synergizes with a disruption to posttranscriptional silencing of RTEs caused by genetic and environmental stress.

Figure 1. Can two hits ignite a fire?

RTE are normally silenced by overlayed systems of repression. First, genomic regions that are rich in RTE sequences are packaged into silent heterochromatin. Heterochromatin formation and maintenance depends on repressive histone modifications, which can be recruited by small RNAs loaded onto an argonaute family member. This loaded RITS complex targets RTE sequences in nascent transcripts. This primary chromatin level silencing appears to be eroded with age [16,27,47,49,53,91,92], perhaps via competition between ADAR and Dicer enzymes for double stranded RNA templates[26]. A secondary system of RTE silencing relies on post transcriptional targeting of RTEs by the RISC complex. This system appears to be stable in the face of normal aging, but is disrupted by TDP-43 proteinopathy[64].

Figure 2. Can the fire spread between glia and neurons?

In healthy glia and neurons, TDP-43 is mostly nuclear in localization (a). For reasons that are not understood, pathological TDP-43 proteinopathy can be initiated, perhaps stochastically in response to cellular stressors (b). When this occurs, TDP-43 is cleared from the nucleus and aggregates in cytoplasmic inclusions that may interfere with argonaute-2 mediated post transcriptional silencing. This leads to a storm of awakened RTEs and ERVs, resulting in DNA damage mediated programmed cell death (c). Non-cell autonomous toxicity of glial cells has been observed in co-culture (see [93] for review). While the mechanisms of such toxicity is not fully explored, the fundamental homology between ERVs and exogenous retroviruses raises the specter of a self amplifying toxic mechanism.