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

Overview

Journal Med Sci Monit

Specialties General Medicine
Pathology

Date 2018 Jun 1

PMID 29851926

Citations 9

Authors

Huiping Tan

Chunlin Wu

Lei Jin

Affiliations

Soon will be listed here.

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.

Citing Articles

Comprehensive profiling of L1 retrotransposons in mouse.

Zhang X, Celic I, Mitchell H, Stuckert S, Vedula L, Han J Nucleic Acids Res. 2024; 52(9):5166-5178.

PMID: 38647072 PMC: 11109951. DOI: 10.1093/nar/gkae273.

Repetitive elements in aging and neurodegeneration.

Copley K, Shorter J Trends Genet. 2023; 39(5):381-400.

PMID: 36935218 PMC: 10121923. DOI: 10.1016/j.tig.2023.02.008.

The Role of Transposable Elements of the Human Genome in Neuronal Function and Pathology.

Chesnokova E, Beletskiy A, Kolosov P Int J Mol Sci. 2022; 23(10).

PMID: 35628657 PMC: 9148063. DOI: 10.3390/ijms23105847.

Analysis of LINE1 Retrotransposons in Huntington's Disease.

Floreani L, Ansaloni F, Mangoni D, Agostoni E, Sanges R, Persichetti F Front Cell Neurosci. 2022; 15:743797.

PMID: 35095420 PMC: 8795916. DOI: 10.3389/fncel.2021.743797.

DNA Methylation in Huntington's Disease.

Zsindely N, Siagi F, Bodai L Int J Mol Sci. 2021; 22(23).

PMID: 34884540 PMC: 8657460. DOI: 10.3390/ijms222312736.

References

Neto J, Lee J, Afridi A, Gillis T, Guide J, Dempsey S . Genetic Contributors to Intergenerational CAG Repeat Instability in Huntington's Disease Knock-In Mice. Genetics. 2016; 205(2):503-516. PMC: 5289832. DOI: 10.1534/genetics.116.195578. View

Yang S, Wei W, Ouyan Q, Jiang Q, Zou Y, Qu W . Interleukin-12 activated CD8 T cells induces apoptosis in breast cancer cells and reduces tumor growth. Biomed Pharmacother. 2016; 84:1466-1471. DOI: 10.1016/j.biopha.2016.10.046. View

Zhang H, Liu J, Tai Y, Zhang X, Zhang J, Liu S . Identification and characterization of L1-specific endo-siRNAs essential for early embryonic development in pig. Oncotarget. 2017; 8(14):23167-23176. PMC: 5410294. DOI: 10.18632/oncotarget.15517. View

Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C . Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell. 1996; 87(3):493-506. DOI: 10.1016/s0092-8674(00)81369-0. View

Kilkenny C, Browne W, Cuthill I, Emerson M, Altman D . Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. Osteoarthritis Cartilage. 2012; 20(4):256-60. DOI: 10.1016/j.joca.2012.02.010. View

Li G, Ying L, Wang H, Wei S, Chen J, Chen Y . Rac1b enhances cell survival through activation of the JNK2/c-JUN/Cyclin-D1 and AKT2/MCL1 pathways. Oncotarget. 2016; 7(14):17970-85. PMC: 4951264. DOI: 10.18632/oncotarget.7602. View

Muotri A, Chu V, Marchetto M, Deng W, Moran J, Gage F . Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature. 2005; 435(7044):903-10. DOI: 10.1038/nature03663. View

Lewandowski N, Bordelon Y, Brickman A, Angulo S, Khan U, Muraskin J . Regional vulnerability in Huntington's disease: fMRI-guided molecular analysis in patients and a mouse model of disease. Neurobiol Dis. 2012; 52:84-93. PMC: 4435974. DOI: 10.1016/j.nbd.2012.11.014. View

Bates G, Dorsey R, Gusella J, Hayden M, Kay C, Leavitt B . Huntington disease. Nat Rev Dis Primers. 2016; 1:15005. DOI: 10.1038/nrdp.2015.5. View

10.

Liu S, Du T, Liu Z, Shen Y, Xiu J, Xu Q . Inverse changes in L1 retrotransposons between blood and brain in major depressive disorder. Sci Rep. 2016; 6:37530. PMC: 5118746. DOI: 10.1038/srep37530. View

11.

Panksepp J . Affective neuroscience of the emotional BrainMind: evolutionary perspectives and implications for understanding depression. Dialogues Clin Neurosci. 2011; 12(4):533-45. PMC: 3181986. View

12.

Bundo M, Toyoshima M, Okada Y, Akamatsu W, Ueda J, Nemoto-Miyauchi T . Increased l1 retrotransposition in the neuronal genome in schizophrenia. Neuron. 2014; 81(2):306-13. DOI: 10.1016/j.neuron.2013.10.053. View

13.

Romorini L, Garate X, Neiman G, Luzzani C, Furmento V, Guberman A . AKT/GSK3β signaling pathway is critically involved in human pluripotent stem cell survival. Sci Rep. 2016; 6:35660. PMC: 5071844. DOI: 10.1038/srep35660. View

14.

Wong J, Vo V, Gorjala P, Fiscus R . Pancreatic-β-cell survival and proliferation are promoted by protein kinase G type Iα and downstream regulation of AKT/FOXO1. Diab Vasc Dis Res. 2017; 14(5):434-449. DOI: 10.1177/1479164117713947. View

15.

Gilels F, Paquette S, Beaulac H, Bullen A, White P . Severe hearing loss and outer hair cell death in homozygous Foxo3 knockout mice after moderate noise exposure. Sci Rep. 2017; 7(1):1054. PMC: 5430619. DOI: 10.1038/s41598-017-01142-3. View

16.

Fang F, Peng T, Yang S, Wang W, Zhang Y, Li H . Lycium barbarum polysaccharide attenuates the cytotoxicity of mutant huntingtin and increases the activity of AKT. Int J Dev Neurosci. 2016; 52:66-74. DOI: 10.1016/j.ijdevneu.2016.05.004. View

17.

Zheng S, Clabough E, Sarkar S, Futter M, Rubinsztein D, Zeitlin S . Deletion of the huntingtin polyglutamine stretch enhances neuronal autophagy and longevity in mice. PLoS Genet. 2010; 6(2):e1000838. PMC: 2816686. DOI: 10.1371/journal.pgen.1000838. View

18.

Liang W, Xu J, Yuan W, Song X, Zhang J, Wei W . APOBEC3DE Inhibits LINE-1 Retrotransposition by Interacting with ORF1p and Influencing LINE Reverse Transcriptase Activity. PLoS One. 2016; 11(7):e0157220. PMC: 4948907. DOI: 10.1371/journal.pone.0157220. View

19.

Rub U, Vonsattel J, Heinsen H, Korf H . The Neuropathology of Huntington´s disease: classical findings, recent developments and correlation to functional neuroanatomy. Adv Anat Embryol Cell Biol. 2016; 217:1-146. View

20.

Vazquez-Manrique R, Farina F, Cambon K, Sequedo M, Parker A, Millan J . AMPK activation protects from neuronal dysfunction and vulnerability across nematode, cellular and mouse models of Huntington's disease. Hum Mol Genet. 2015; 25(6):1043-58. PMC: 4764188. DOI: 10.1093/hmg/ddv513. View