The Significance of LINE-1 in Huntington Disease
Huntington Disease (HD) is an autosomal dominant neurodegenerative disorder characterized by progressive motor impairment, psychiatric disturbances, and cognitive decline1. HD is caused by an expansion of a CAG trinucleotide repeat in the huntingtin gene. The mutant huntingtin protein gains toxic function and results in neurodegeneration, specifically in the striatum2. Current treatment options for Huntington Disease are limited to managing symptoms and quality of life2. There is currently no way to cure or prevent HD. Recent studies into the etiology of HD have focused on the role of LINE-1. Long Interspersed Nuclear Elements 1 (LINE-1) are the most abundant transposable elements in humans1. LINE-1 RNA intermediates are reverse transcribed and inserted into new genomic loci1. ORF1 and ORF2 are the major LINE-1 encoded proteins responsible for retrotransposition. LINE-1 expression and LINE-1 encoded proteins have been identified as promising therapeutic drug targets for cancer, but their utility in HD has not been rigorously examined. A study by Floreani et al, 2022 examined postmortem brains of HD patients and determined the expression of LINE-1 elements. The results showed a statistically significant correlation between LINE-1 expression and the number of CAG repeats1. These findings are significant given that an increase in the number of CAG repeats is associated with earlier onset and greater severity of HD. Other studies have compared the expression of LINE-1 encoded proteins between wild type and HD mice. In these studies, mice with HD had higher levels of ORF1 and ORF2 in the striatum and cortex compared to wild type mice3. Further analysis found that increased ORF2 expression downregulates pro-survival proteins, such as AKT and AMPK3. The role of LINE-1 in neurodegeneration is supported by the finding that increased levels of LINE-1 proteins is seen as the brain ages as well as in other neurogenerative disorders4. A study by Casale et al, 2021 investigated whether blocking retrotransposition of transposable elements with reverse transcriptase inhibitors would affect Drosophila HD models. HD flies treated with reverse transcriptase inhibitors showed decreased genomic instability and increased life span compared to the control group5. The study also showed that the mutant huntingtin protein induces LINE-1 activation by causing widespread heterochromatin decondensation5. Overexpression of LINE-1 encoded proteins downregulates pro-survival proteins, resulting in the neurodegeneration seen in HD. Inhibition of LINE-1 activity with reverse transcriptase inhibitors improved HD symptoms. Thus, LINE-1 might be a promising potential therapeutic target for the treatment of HD.
- Floreani L, Ansaloni F, Mangoni D, et al. Analysis of LINE1 Retrotransposons in Huntington’s Disease. Front Cell Neurosci. 2022;15:743797. Published 2022 Jan 14. doi:10.3389/fncel.2021.743797
- Ghosh R, Tabrizi SJ. Huntington disease. Handb Clin Neurol. 2018;147:255-278. doi:10.1016/B978-0-444-63233-3.00017-8
- Tan H, Wu C, Jin L. A Possible Role for Long Interspersed Nuclear Elements-1 (LINE-1) in Huntington’s Disease Progression. Med Sci Monit. 2018;24:3644-3652. Published 2018 May 31. doi:10.12659/MSM.907328
- Sur D, Kustwar RK, Budania S, et al. Detection of the LINE-1 retrotransposon RNA-binding protein ORF1p in different anatomical regions of the human brain. Mob DNA. 2017;8:17. Published 2017 Nov 22. doi:10.1186/s13100-017-0101-4
- Casale AM, Liguori F, Ansaloni F, et al. Transposable element activation promotes neurodegeneration in a Drosophila model of Huntington’s disease. iScience. 2021;25(1):103702. Published 2021 Dec 28. doi:10.1016/j.isci.2021.103702