Aberrantly High Levels of Somatic LINE-1 Expression and Retrotransposition in Human Neurological Disorders

Abstract

Retrotransposable elements (RTEs) have actively multiplied over the past 80 million years of primate evolution, and as a consequence, such elements collectively occupy ∼ 40% of the human genome. As RTE activity can have detrimental effects on the human genome and transcriptome, silencing mechanisms have evolved to restrict retrotransposition. The brain is the only known somatic tissue where RTEs are de-repressed throughout the life of a healthy human and each neuron in specific brain regions accumulates up to ∼13.7 new somatic L1 insertions (and perhaps more). However, even higher levels of somatic RTE expression and retrotransposition have been found in a number of human neurological disorders. This review is focused on how RTE expression and retrotransposition in neuronal tissues might contribute to the initiation and progression of these disorders. These disorders are discussed in three broad and sometimes overlapping categories: 1) disorders such as Rett syndrome, Aicardi-Goutières syndrome, and ataxia-telangiectasia, where expression/retrotransposition is increased due to mutations in genes that play a role in regulating RTEs in healthy cells, 2) disorders such as autism spectrum disorder, schizophrenia, and substance abuse disorders, which are thought to be caused by a combination of genetic and environmental stress factors, and 3) disorders associated with age, such as frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and normal aging, where there is a time-dependent accumulation of neurological degeneration, RTE copy number, and phenotypes. Research has revealed increased levels of RTE activity in many neurological disorders, but in most cases, a clear causal link between RTE activity and these disorders has not been well established. At the same time, even if increased RTE activity is a passenger and not a driver of disease, a detrimental effect is more likely than a beneficial one. Thus, a better understanding of the role of RTEs in neuronal tissues likely is an important part of understanding, preventing, and treating these disorders.

Keywords: L1; LINE; SINE; brain; neurological disease; retrotransposition; somatic.

Figure 1

L1 retrotransposition mechanism. (A) A retrotransposition-competent L1 is 6 kb in length and consists of a 5′ UTR, open reading frame 1 (ORF1), open reading frame 2 (ORF2), a 3′ UTR and a poly(A) tail (Moran et al., 1996; Babushok and Kazazian, 2007; Rosser and An, 2012). Within the 5′UTR there is a promoter on the sense strand that drives the expression of full-length L1s as well as an antisense promoter. ORF1 codes for a protein (ORF1p) with RNA binding and nucleic acid chaperone activity, and ORF2 encodes for a protein (ORF2p) with endonuclease and reverse transcriptase activities. (B) After transcription, the L1 mRNA moves to the cytoplasm where it is translated. The resulting ORF1p and ORF2p preferentially bind to the L1 mRNA that produced them (cis-preference), forming an L1-RNP that is imported back to the nucleus. Insertion occurs through target primed reverse transcription in which the ORF2p endonuclease nicks a DNA strand at a 5′TTTT/AA3′ consensus site, thereby exposing a 3′ hydroxyl that serves as a priming site for the ORF2p reverse transcriptase to generate a cDNA copy from the L1 mRNA. It is believed that a similar process occurs on the other strand of DNA to complete the L1 insertion process. Only a fraction of the L1 insertions in humans are full-length (6 kb), as new insertions often are 5′ truncated due to DNA repair pathways that recognize and disrupt reverse transcription (Coufal et al., 2011).

Figure 2

L1 Silencing (A) Methylation of CpG islands in the promoters of L1s to silence expression. L1 silencing is maintained by MeCP2p binding to methylated cytosines in the CpG island core of the L1 promoter. (B) The transcription factor SOX2 is downregulated during neural stem cell differentiation. The SOX2 downregulation, combined with chromatin remodeling and promoter demethylation, decrease MeCP2p binding to the L1 promoter. Simultaneous activation of the canonical WNT pathway results in stimulation of L1 expression. L1 de novo retrotransposition then can occur in the healthy human brain in neural progenitor cells (NPCs) and during neurogenesis, including in adults. (C) Retrotransposition does not just occur during differentiation but can occur in mature non-dividing neuronal cells. (D) In Rett syndrome, mutation of the X-linked gene methyl CpG binding protein 2 (MECP2) leading to abnormal epigenetic regulation such that L1 promoters are not silenced. (E). The reduced regulation of L1 results in more expression and increased retrotransposition in neural progenitor cells (NPCs). (F) The increased retrotransposition events can continue to occur in mature non-dividing neuronal cells.