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

Abstract

BackgroundAmyotrophic 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.MethodsFor 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.ResultsWe 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (10.1186/s13024-018-0275-3) contains supplementary material, which is available to authorized users.

Epigenetic Components of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Uncover Potential Transposable Element Activation

“…122 Interestingly, ME/CFS and comorbid diseases have been repeatedly associated with stresses of several types, including infections, and reports of altered cytokine profiles are numerous. 16e23,123e125 Thus, it seems plausible that TE aberrant activation is at the core of the molecular mechanisms involved in ME/CFS, a possibility already established for other immune and neurologic diseases such as lupus, 43 multiple sclerosis, 44 or amyotrophic lateral sclerosis 126,127 and yet under explored for ME/CFS. 128,129 In addition, as reviewed in an earlier section, ME/ CFS blood cell genomes present patterns of differential DNA methylation with respect to healthy subjects 28e37,58,71 that might translate into aberrant chromatin topology and abnormal TE transcriptional activation, perhaps leading to element transposition.…”

“…We recommend that future ME/ CFS transcriptomic studies avoid RepeatMasker filters to start documenting the potential role of TEs in the disease. In addition, approaches aimed at measuring TE activation impact in ME/CFS such as discriminating microarrays, Northern blot, or RT-qPCR amplifications 126,144,145 should be pursued.…”

HIV-1 Rev interacts with HERV-K RcREs present in the human genome and promotes export of unspliced HERV-K proviral RNA

“…Thus it will be of clear interest to further define the RcREs present in HERV-K mRNAs that are expressed in HIV infected individuals, especially those with strong anti-HERV-K immune responses, and to determine whether the Rev proteins expressed in these individuals can function in conjunction with these RcREs. It has also been reported that the 3q12.3 provirus is actively transcribed in patients with Amyotropic Lateral Sclerosis (ALS) (57) and although this remains controversial, it has been proposed that HERVs plays a pathophysiological role in this lethal disease (for a review see (58). Some HIV-infected patients develop neurological manifestations that resemble classical ALS, although it occurs at a younger age and there has been reports of improvement following the initiation of antiretroviral therapy (59).…”

Safety and tolerability of Triumeq in amyotrophic lateral sclerosis: the Lighthouse trial

“…Evidence linking retroviruses and HERV-K to ALS includes increased nonspecific reverse transcriptase activity in the blood and cerebrospinal fluid of ALS patients compared to relatives and controls (13)(14)(15)(16), and increased levels of different transcripts of HERV-K in brains of ALS patients compared to controls (17), although not shown in all studies for the gag gene (18). In one study, active loci of HERV-K were found in ALS and HERV-K expression was strongly correlated with TDP-43 expression (19).…”