Transcriptional profiling of HERV-K(HML-2) in amyotrophic lateral sclerosis and potential implications for expression of HML-2 proteins
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Amyotrophic lateral sclerosisHuman endogenous retrovirusRetrotransposonReverse transcriptionEnvelope protein
Mayer, J., Harz, C., Sanchez, L., Pereira, G. C., Maldener, E., Heras, S. R., ... & García-Pérez, J. L. (2018). Transcriptional profiling of HERV-K (HML-2) in amyotrophic lateral sclerosis and potential implications for expression of HML-2 proteins. Molecular neurodegeneration, 13(1), 39.
SponsorshipJ.L.G. was funded by the NIH National Institute of Neurological Disorders and Stroke (1R03NS087290–01) and Eunice Kennedy Shriver National Institute of Child Health and Human Development (1R21HD083915-01A1), and the ALS Therapy Alliance (2013-F-067). The J.L.G.-P. lab is supported by CICE-FEDERP12- CTS-2256, Plan Nacional de I + D + I 2008–2011 and 2013–2016 (FISFEDER- PI14/02152), PCIN-2014-115-ERA-NET NEURON II, the European Research Council (ERC-Consolidator ERC-STG-2012-233764), by an International Early Career Scientist grant from the Howard Hughes Medical Institute (IECS-55007420), by The Wellcome Trust-University of Edinburgh Institutional Strategic Support Fund (ISFF2) and by a private donation by Ms. Francisca Serrano (Trading y Bolsa para Torpes, Granada, Spain).
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. About 90% of ALS cases are without a known genetic cause. The human endogenous retrovirus multi-copy HERV-K(HML-2) group was recently reported to potentially contribute to neurodegeneration and disease pathogenesis in ALS because of transcriptional upregulation and toxic effects of HML-2 Envelope (Env) protein. Env and other proteins are encoded by some transcriptionally active HML-2 loci. However, more detailed information is required regarding which HML-2 loci are transcribed in ALS, which of their proteins are expressed, and differences between the disease and non-disease states. We identified 24 different transcribed HML-2 loci. Some of those loci are transcribed at relatively high levels. However, significant differences in HML-2 loci transcriptional activities were not seen when comparing ALS and controls. Likewise, overall HML-2 transcript levels, as determined by RT-qPCR, were not significantly different between ALS and controls. Indeed, we were unable to detect full-length HML-2 Env protein in ALS and control tissue samples despite reasonable sensitivity. Rather our analyses suggest that a number of HML-2 protein variants other than full-length Env may potentially be expressed in ALS patients. Our results expand and refine recent publications on HERV-K(HML-2) and ALS. Some of our results are in conflict with recent findings and call for further specific analyses. Our profiling of HML-2 transcription in ALS opens up the possibility that HML-2 proteins other than canonical full-length Env may have to be considered when studying the role of HML-2 in ALS disease.