Transcriptional profiling of HERV-K(HML-2) in amyotrophic lateral sclerosis and potential implications for expression of HML-2 proteins

Jens Mayer, Christian Harz, Laura Sanchez, Gavin C. Pereira, Esther Maldener, Sara R. Heras, Lyle W. Ostrow, John Ravits, Ranjan Batra, Eckart Meese, Jose Luis García-Pérez, John L. Goodier

Research output: Contribution to journalArticle

Abstract

Background: 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. Methods: For brain and spinal cord tissue samples from ALS patients and controls, we identified transcribed HML-2 loci by generating and mapping HML-2-specific cDNA sequences. We predicted expression of HML-2 env gene-derived proteins based on the observed cDNA sequences. Furthermore, we determined overall HML-2 transcript levels by RT-qPCR and investigated presence of HML-2 Env protein in ALS and control tissue samples by Western blotting. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Article number39
JournalMolecular neurodegeneration
Volume13
Issue number1
DOIs
StatePublished - Aug 2 2018

Keywords

  • Amyotrophic lateral sclerosis
  • Envelope protein
  • Gag protein
  • HERV-K(HML-2)
  • Human endogenous retrovirus
  • Provirus
  • Retrotransposon
  • Reverse transcription

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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    Mayer, J., Harz, C., Sanchez, L., Pereira, G. C., Maldener, E., Heras, S. R., Ostrow, L. W., Ravits, J., Batra, R., Meese, E., García-Pérez, J. L., & Goodier, 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]. https://doi.org/10.1186/s13024-018-0275-3