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

Med Sci Monit. 2018 May 31:24:3644-3652. doi: 10.12659/MSM.907328.

Abstract

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.

MeSH terms

  • Animals
  • DNA Methylation
  • Disease Models, Animal
  • Disease Progression
  • Endonucleases / analysis
  • Endonucleases / genetics
  • Female
  • Humans
  • Huntington Disease / genetics*
  • Long Interspersed Nucleotide Elements / genetics
  • Long Interspersed Nucleotide Elements / physiology*
  • Male
  • Mice
  • Mice, Transgenic
  • Neurons / metabolism
  • Phosphoproteins / genetics
  • RNA-Directed DNA Polymerase / analysis
  • RNA-Directed DNA Polymerase / genetics
  • Retroelements / genetics
  • Signal Transduction
  • Transcription Factors / analysis
  • Transcription Factors / genetics

Substances

  • Med14 protein, mouse
  • ORF2 protein, human
  • Phosphoproteins
  • Retroelements
  • Transcription Factors
  • RNA-Directed DNA Polymerase
  • Endonucleases