Scientists Get a Jump on Retrotransposons and C9orf72 ALS/FTD

Wreaking genetic havoc? More than 270 repetitive elements might be reactivated in the frontal cortex of the brain in people with C9orf72/ALS according to a RNA seq analysis.[Courtesy of Prudencio et al., 2017, Human Molecular Genetics].

Nearly half of the human genome consists of retrotransposable elements, kept silent through multiple mechanisms. But according to a new RNAseq analysis led by Mayo Clinic’s Leonard Petrucelli in Florida, more than 150 of these repetitive LTR and LINE elements may become re-activated and contribute to neuronal toxicity in C9orf72 ALS, the most common known cause of the disease.

The findings build on previous studies led by National Institute of Health’s Avindra Nath in Maryland and Stonybrook University’s Joshua Dubnau in New York that suggest that the derepression of at least some of these elements may contribute to ALS including sporadic disease (see October 2015 and March 2017 news; Krug et al., 2017; Li et al., 2015; Li et al., 2013).

The study is published on June 16 in Human Molecular Genetics.

The analysis found that increased levels of expression of more than 270 repetitive elements could be detected in the frontal cortex compared to non-C9orf72 ALS cases, including human endogenous retroviruses (HERVs). What’s more, a subset of these elements appear to be upregulated in this region of the brain in people with C9orf72 ALS/FTD and C9orf72 FTD opening up the possibility that these changes may contribute, in part, to frontal involvement in FTD forms of the disease.

A key question is how these repetitive elements may become activated in ALS/FTD and whether this upregulation plays a key role in the disease. According to studies of a Drosophila model of ALS led by Joshua Dubnau, this re-activation may be mediated by TDP-43 and may contribute to neurotoxicity (see March 2017 news; Krug et al., 2017). But Petrucelli’s team saw no significant correlation between expression of these elements and TDP-43 pathology in the brain of people with ALS/FTD or FTD.

Studies are ongoing. Stay tuned.


To learn more about retrotransposons, including emerging strategies to tackle them, check out  Retrotransposons Jump Into the Mix in ALS.

Featured Paper

Prudencio M, Gonzales PK, Cook CN, Gendron TF, Daughrity LM, Song Y, Ebbert MTW, van Blitterswijk M, Zhang YJ, Jansen-West K, Baker MC, DeTure M, Rademakers R, Boylan KB, Dickson DW, Petrucelli L, Link CD. Repetitive element transcripts are elevated in the brain of C9orf72 ALS/FTLD patients. Hum Mol Genet. 2017 Jun 16. [PubMed].


Li W, Lee MH, Henderson L, Tyagi R, Bachani M, Steiner J, et al. Human endogenous retrovirus-K contributes to motor neuron disease. Sci Transl Med. 2015; 7(307):307ra153. [PubMed].

Krug L, Chatterjee N, Borges-Monroy R, Hearn S, Liao WW, Morrill K, Prazak L, Rozhkov N, Theodorou D, Hammell M, Dubnau J. Retrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS. PLoS Genet. 2017 Mar 16;13(3):e1006635. [PubMed].

Li W, Prazak L, Chatterjee N, Grüninger S, Krug L, Theodorou D, Dubnau J. Activation of transposable elements during aging and neuronal decline in Drosophila. Nat Neurosci. 2013 May;16(5):529-31. [PubMed].



c9orf72 disease-als disease-ftd HERV-K retrotransposon tdp-43
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