A Possible Role for Long Interspersed Nuclear Elements-1 (LINE-1) in Huntington’s Disease Progression

Abstract

BackgroundRecent studies have shown that increased mobilization of Long Interspersed Nuclear Elements-1 (L1) can promote the pathophysiology of multiple neurological diseases. However, its role in Huntington’s disease (HD) remains unknown.Material/MethodsR6/2 mice – a common mouse model of HD – were used to evaluate changes in L1 mobilization. Pyrosequencing was used to evaluate methylation content changes. L1-ORF1 and L1-ORF2 expression analysis were evaluated by RT-PCR and immunoblotting. Changes in pro-survival signaling were evaluated by L1-ORF overexpression studies and validated in the mouse model by immunohistochemistry and immunoblotting.ResultsWe found an increased mobilization of L1 elements in the caudate genome of R6/2 mice (p<0.05) – a common mouse model of HD – but not in wild-type mice. Subsequent pyrosequencing and expression analysis showed that the L1 elements were hypomethylated and their respective ORFs were overexpressed in the affected tissues. In addition, a significant decrease in the pro-survival proteins such as the phosphoproteins of AKT target proteins, mTORC1 activity, and AMPK alpha levels was observed with the increase in the expression L1-ORF2.ConclusionsThese findings indicate that hyperactive retrotransposition of L1 triggers a downstream signaling pathway affecting the neuronal survival pathways via downregulation of mTORC1 activity and AMPKalpha and increasing apoptosis in neurons.

Properties of LINE-1 proteins and repeat element expression in the context of amyotrophic lateral sclerosis

“…Thus, it has been proposed that L1 activity contributes to neuronal plasticity [28]. Elevated L1 retrotransposition has also been reported for several human neurological conditions, including ataxia telangiectasia [29], Rett syndrome [30], autism [31], schizophrenia [32, 33], and major depressive disorder [34], as well as in neuronal cell lines or brains of patients exposed to opioids [35–37], and in brains of a mouse model of Huntington's disease [38] and hippocampi of mice following novel exploration [39] or diminished maternal care [40]. However, some of these studies relied solely on DNA amplification by quantitative (q)PCR or digital droplet PCR to compare L1 insertion copy differences between test and normal states, strategies that may fail to distinguish between bona fide genomic L1 insertions and contaminating extrachromosomal L1-derived nucleic acids.…”

DNA Methylation in Huntington’s Disease

“…Activation of L1, in turn, might play a role in HD pathology by modulating several survival signaling pathways. This theory is supported by findings showing that similarly to the effects of mHtt expression in R6/2 mice L1 ORF2 overexpression in 293T cells led to downregulation of mTOR1 activity (reduced pS6 and AMPKα levels) and decreased phosphorylation levels of several targets of the pro-survival kinase AKT [ 69 ].…”

Brain organoids and insights on human evolution

“…L1 elements are different between humans and other animals 40 . Evidence that L1 activity could contribute to other neurological disorders, such as Huntington’s disease 41 , Down syndrome, and Alzheimer’s disease 42 , and aging 43 has recently been provided. It is an attractive hypothesis that the sequence-specific L1 differences might contribute to several human conditions, creating the potential for unconventional treatments using reverse transcriptase inhibitors, such as anti-HIV drugs.…”