Human Endogenous Retrovirus-K and TDP-43 Expression Bridges ALS and HIV Neuropathology

Douville, Renée N.; Nath, Avindra

doi:10.3389/fmicb.2017.01986

Cited by 43 publications

(38 citation statements)

References 81 publications

(108 reference statements)

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“…TDP-43 protein aggregation has emerged as a unifying pathological marker of a majority of ALS and frontotemporal lobar degeneration (FTLD) cases [ 44 ]. Correlation of TDP-43 and HERV-K(HML-2) RT and pol expression in brain tissues has been reported [ 42 , 45 ], although that link is controversial. Although Li et al [ 46 ] reported TDP-43 protein bound the HERV-K LTR with an attendant increase in HERV-K transcription and RT activity, Manghera et al [ 47 ] found that wild-type TDP-43 binds the HML-2 LTR without altering transcription, while mutant TDP-43 promotes HML-2 RT protein aggregation resulting in its clearance from astrocytes but not neurons.…”

Section: Introductionmentioning

confidence: 99%

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

Mayer

Harz

Sánchez

et al. 2018

Mol Neurodegeneration

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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.

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Section: Introductionmentioning

confidence: 99%

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

Mayer

Harz

Sánchez

et al. 2018

Mol Neurodegeneration

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“…The immune-mediated retrotranscription of specific HERVs was shown possibly to negatively influence the outcome of CNS disorders (Douville et al, 2011;Douville and Nath, 2017;Kremer et al, 2013;Küry et al, 2018). While our work unravels the putative evolutionary-determined advantage conferred by the immune/MER41/cognition pathway in human, it also points to the potential weaknesses that are inherent to such a pathway.…”

Section: Accordinglymentioning

confidence: 74%

The promoter regions of intellectual disability-associated genes are uniquely enriched in LTR sequences of the MER41 primate-specific endogenous retrovirus: an evolutionary connection between immunity and cognition

Nataf

Uriagereka

Benítez‐Burraco

2018

Preprint

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Social behavior and neuronal connectivity in rodents have been shown to be shaped by the prototypical T lymphocyte-derived pro-inflammatory cytokine Interferon-gamma (IFN). It has also been demonstrated that STAT1 (Signal Transducer And Activator Of Transcription 1), a transcription factor (TF) crucially involved in the IFN pathway, binds consensus sequences that, in humans, are located with a high frequency in the LTRs (Long Terminal Repeats) of the MER41 family of primate-specific HERVs (Human Endogenous Retrovirus). However, the putative role of an IFN/STAT1/MER41 pathway in human cognition and/or behavior is still poorly documented. Here, we present evidence that the promoter regions of intellectual disability-associated genes are uniquely enriched in LTR sequences of the MER41 HERVs. This observation is specific to MER41 among more than 130 HERVs examined. Moreover, we have not found such a significant enrichment in the promoter regions of genes that associate with autism spectrum disorder (ASD) or schizophrenia. Interestingly, ID-associated genes exhibit promoter-localized MER41 LTRs that harbor TF binding sites (TFBSs) for not only STAT1 but also other immune TFs such as, in particular, NFKB1 (Nuclear Factor Kappa B Subunit 1) and STAT3 (Signal Transducer And Activator Of Transcription 3). Moreover, IL-6 (Interleukin 6) rather than IFN, is identified as the main candidate cytokine regulating such an immune/MER41/cognition pathway. Of note, functionally-relevant differences between humans and chimpanzees are observed regarding the 3 main components of this pathway: i) the protein sequences of immunes TFs binding MER41 LTRs, ii) the insertion sites of MER41 LTRs in the promoter regions of ID-associated genes and iii) the protein sequences of the targeted ID-associated genes. Finally, a survey of the human proteome has allowed us to map a protein-protein network which links the identified immune/MER41/cognition pathway to FOXP2 (Forkhead Box P2), a key TF involved in the emergence of human speech.

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“…Based on experiments in cultured human cells, Drosophila (fruit fly) and mice TDP-43 models, it is possible that HERV RT protein levels are being increased by TDP-43 through a not yet clear mechanism (11,(24)(25)(26). Interestingly, HIV infection of the CNS also leads to neuroinflammation, increased TDP-43 expression, and increased HERV expression (27).…”

Section: Mechanismsmentioning

confidence: 99%

ALSUntangled 45: Antiretrovirals

2018

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

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Human Endogenous Retrovirus-K and TDP-43 Expression Bridges ALS and HIV Neuropathology

Cited by 43 publications

References 81 publications

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

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

The promoter regions of intellectual disability-associated genes are uniquely enriched in LTR sequences of the MER41 primate-specific endogenous retrovirus: an evolutionary connection between immunity and cognition

ALSUntangled 45: Antiretrovirals

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