A Possible Role for Long Interspersed Nuclear Elements-1 (LINE-1) in Huntington’s Disease Progression
Huiping Tan, Chunlin Wu, Lei Jin
(Reproductive Medicine Center, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (mainland))
Med Sci Monit 2018; 24:3644-3652
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, Cell Survival, Long Interspersed Nuclear Elements-1, Huntington’s disease