31 May 2018 : Animal Research
A Possible Role for Long Interspersed Nuclear Elements-1 (LINE-1) in Huntington’s Disease ProgressionHuiping Tan1ABCDEFG, Chunlin Wu2ABCDE, Lei Jin1ACDEF*
Med Sci Monit 2018; 24: ANS3644-3652
BACKGROUND: Recent 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 AND METHODS: R6/2 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.
RESULTS: We 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.
CONCLUSIONS: These 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.
Keywords: AMP-Activated Protein Kinases, Long Interspersed Nuclear Elements-1, Huntington’s disease
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