Tau Aggregates Awaken Genetic Relics in the Brain

Tau pathology in the brain may awaken dormant transposable elements throughout the genome, according to a study in the June 5 Cell Reports. Transposable elements are snippets of DNA, including retrovirus remnants, that jumped from genome to genome throughout evolution. They are normally kept under wraps by condensed tracts of heterochromatin, but researchers led by Joshua Shulman of Baylor College of Medicine, Houston, reported that something about neurofibrillary tangles triggers their expression. The authors propose that the tau aggregates somehow open up chromatin to the transcription machinery. Aberrantly active transposons have been reported in other neurodegenerative diseases as well. The consequences of rousing long-silenced transposable elements remain unclear.

  • Tau burden in the human brain correlates with transcription of transposons.
  • Tangles correlate with active chromatin around transposable elements.
  • Fly models support this connection to transposon activation.

Avindra Nath of the National Institutes of Health in Bethesda, who reported transposon activation in amyotrophic lateral sclerosis, considers Shulman’s findings in AD intriguing but preliminary. If tied to neurodegeneration, then transposon activation by tau could offer a fresh therapeutic target to pursue, he said.

Nearly half of the human genome comprises transposable elements, a.k.a transposons (Lander et al., 2001). Most of them, including endogenous retroviruses (ERVs), lie dormant, swaddled within swaths of impenetrable heterochromatin. However, an emerging body of data suggests that these sleeping sequences can be transcribed, and perhaps even mobilized, in the context of aging and neurodegenerative diseases, including ALS and multiple sclerosis (Dolei, 2018; Li et al., 2012; Oct 2015 news).

Tau Awakens Transposons.

Toxic tau correlated with transcription of dormant transposable elements, both in the human brain and in transgenic fly models. [Courtesy of Guo et al., Cell Reports, 2018.]

Co-first authors Caiwei Guo and Hyun-Hwan Jeong investigated if tau tangles in the AD brain can rouse transposons. They examined data from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP). These prospective cohort studies track participants’ physical and cognitive health during life, and evaluate neuropathology and brain gene expression after death. The researchers analyzed RNA sequencing data from the dorsolateral prefrontal cortices of 636 volunteers. They developed a computational algorithm to search for transcribed transposons, identified 547 of them, and tested for links to tau pathologic burden.

Expression of nine transposons significantly correlated with the density of tau tangles. These included transposons of different evolutionary origins, or clades, including long interspersed nuclear elements 1 (LINE1s), short interspersed nuclear elements (SINEs), and endogenous retroviruses (ERVs). Searching more broadly, the researchers considered groups of related transposons. They found that ERV1, 2, 3, and LINE1 clades correlated with tau pathology at a group level. In addition, activation of transposons from the three ERV clades correlated with lower cognitive performance in the year leading up to death.

To determine if tau pathology was responsible for the transposon expression, the researchers turned to fruit fly models. They first used RT-PCR to measure expression of 12 known transposons in Drosophila that expressed human wild-type tau, or human tau harboring the FTD-associated R406W mutation. As they age, both these strains accumulate hyperphosphorylated, misfolded tau in the brain and lose neurons. Three of the transposons—named gypsy, copia, and het-a—were expressed up to 10-fold higher in one or both of the transgenics compared with normal flies. These differences emerged when the flies were only one day old, but, at least for the copia transposon, expression continued to rise as the flies aged to 20 days, which is considered old for a fruit fly. To confirm and extend these findings, the researchers performed a separate RNA-Seq analysis to quantify transposon expression in 20-day-old control flies versus flies expressing wild-type human tau. Again, expression of gypsy, copia, and het-a was higher in the transgenics. Of 162 other transposon transcripts identified in the analysis, 64 were more highly expressed in the tau model.

What might transcription of transposons do to neurons? Shulman has yet to address that question. He speculates that these transcripts, some of which resemble viral RNA, might trigger innate immune responses in the brain and lead to the type of neuroinflammatory responses observed in many neurodegenerative diseases, including AD. If the transposons also mobilize, they could insert themselves into other places in the genome, and mutate other genes in the process.

From Relaxation to Neurodegeneration.

In the proposed model, tau pathology relaxes chromatin. This leads to transposon transcription and possible mobilization, which could activate innate inflammatory responses and DNA damage, respectively. [Courtesy of Guo et al., Cell Reports, 2018.]

Christopher Link, University of Colorado, Boulder, agreed that innate immune activation could be a likely mode of toxicity. He proposed that because their sequences are repetitive in nature, transposons may form double-stranded RNA hybrids, which tend to alarm innate immune cells. Along those lines, Link told Alzforum that unpublished observations from his lab indicate that such aberrant transcription, when set off by TDP-43 pathology, incites astrogliosis.

As to how tau might incite transposon expression in the first place, Shulman said the question is unanswered. Previously, Bess Frost of the University of Texas Health in San Antonio, reported that tau somehow instigates widespread chromatin opening (Frost et al., 2014; Apr 2017 news). Philip de Jager, a co-author on Shulman’s paper, has a manuscript on bioRχiv supporting this idea (Klein et al., 2018). For his part, Shulman has found markers of active chromatin around one of the expressed ERVs in the ROSMAP brain samples. Frost told Alzforum she has a paper accepted at Nature Neuroscience that corroborates and extends the idea that tau activates transposons.

Peter Davies of Albert Einstein College of Medicine in New York found the study intriguing, especially in light of emerging evidence pointing to transposon activation in other neurodegenerative diseases. However, he raised several key questions. “For a tauist, there is a ‘black box’ to this story. What is it about tau that might trigger such a catastrophic response in a neuron?” he asked. Davies also found it difficult to assess whether the activation of transposons was a specific response or a general one. “Is [transcription from these loci] a sign of a sick cell, or a critical step in tau-mediated cell death? The complexity of the transcriptional activation will make this difficult to dissect,” he said.

On that note, Josh Dubnau of Stony Brook University School of Medicine in New York, who also reported transposon transcription in ALS, lamented the common practice of disregarding transposon sequences in genomic studies. “That has to stop, because evidence is accumulating that retrotransposable elements (RTEs) may contribute to many age-related diseases, including cancer and neurodegeneration, and may even contribute to normal aging,” he wrote. “By focusing on RTE sequences, these authors have in fact found strong evidence that many RTEs are highly expressed in AD brains and in a Drosophila model of tau pathology. It now becomes important to ask if such expression is a cause of or a consequence of the disease state.”—Jessica Shugart

Comments

  1. I first heard of the idea of transposon mobilization in human brain disease from Joshua Dubnau, then at Cold Spring Harbor. Josh and his colleagues published a paper providing evidence for activation of transposable elements in association with TDP pathology in ALS and FTLD (Li et al., 2012). Here, Guo et al. use a large RNA-seq dataset to show correlations between tau pathology and activation of transcription from transposable element loci in human brain, and in flies transgenic for human tau. This is an intriguing paper, reinforcing an idea which sounds less novel now than it did in 2012.

    For a tauist, there is a "black box" to this story. What is it about tau that might trigger such a catastrophic response in a neuron? The human brain work correlates transposon activation with neurofibrillary tangle formation, but in Drosophila such aggregation of over expressed human tau is rare, and cell death usually occurs without tau filament formation. It is also far from clear how transcription from these loci will relate to cell death. Is this a sign of a sick cell - or a critical step in tau-mediated cell death? The complexity of the transcriptional activation will make this difficult to dissect.

    View all comments by Peter Davies

  2. Almost half of our DNA content consists of ancient virus like elements called retrotransposons (RTEs). RTEs are capable of copying themselves and then reinserting their new copies into our chromosomes. Our genomes invest heavily in keeping this half of our DNA quiescent because the wholesale activation of RTEs is incredibly damaging to the cell in a variety of ways.

    There is now accumulating evidence to support the hypothesis that RTEs may contribute to the cellular toxicity that causes a variety of age-dependent neurodegenerative disorders, including amyotrophic lateral sclerosis, frontotemporal dementia, and macular degeneration.  This study adds evidence that RTEs may be at the heart of AD.

    It is important to recognize that although RTEs make up a vast fraction of our DNA, they have been almost completely ignored by human genetics (and by most geneticists studying animal models) until recently.  The reason for this is that the standard computational algorithms for examining troves of genomic data begin by throwing out almost all the RTE sequences before the analysis really gets going. That has to stop because evidence is accumulating that RTEs may contribute to many age-related diseases, including cancer and neurodegeneration, and even normal aging.  So it now becomes quite important to stop ignoring RTE sequences.  By focusing on RTE sequences, these authors have, in fact, found strong evidence that many RTEs are highly expressed in AD brains and in a Drosophila model of tau pathology.  It now becomes important to ask if such expression is a cause of or a consequence of the disease state.

    View all comments by Josh Dubnau

  3. This study investigated whether transposable elements (TEs) are differentially expressed in association with tau pathology in Alzheimer's disease (AD), using human post-mortem brain samples and a Drosophila model of AD. With regards to the human analysis, the cohort size (n=636) is impressive, and the observation of association with neurofibrillary tangles is intriguing. I also very much appreciated the circumspect discussion.

    At the same time, I have a lot of questions. For example, it is not clear to me how big an absolute expression change was required for a given TE group to be elevated and considered significantly associated with a given tau pathology parameter in the linear regression statistics. 2%, 20% or 200%? As the authors note, the only autonomous human TE (L1Hs) was not at all associated with tangles, making it unclear how TE activity would contribute to genomic instability. The authors propose instead that some TE families are activated by chromatin relaxation promoted by tau pathology, which has been reported previously, and this makes more sense.

    It is also interesting that the 5' end of one of the significant L1 subfamily hits (e.g. L1MB4_5 - copy number I think < 100) is significantly associated with tangles, whilst the 3' end of the same subfamily (L1MB4 - copy number ~9,200) is not. Why is that and how does it fit with the chromatin relaxation model? It would be useful to know the copy numbers of all of the human TE families with significant associations in the study.

    Finally, I would be interested to see if these batch results replicate if one simply aligns the RNA-seq directly to the genome and intersects those data with the genomic coordinates of each individual TE; all except for the youngest TE subfamilies are highly mappable with the length and quality of RNA-seq reads available here, and this could generate some interesting examples of individual TE copies that are associated with pathology. In sum, the study is preliminary but very interesting and leads to many additional questions.

    View all comments by Geoff Faulkner

  4. This paper by Guo and colleagues on the activation of transposable elements, and, in particular, of the LTR of HERV-Fc1 endogenous retrovirus in tau-associated lesions of human brains from patients who died with Alzheimer’s disease is interesting, as AD prevalence is increasing in elderly. Tau mechanisms of action were not specified in the paper, but a recent review notes that “although tau protein is well-known for its key role in stabilizing and organization of axonal microtubule network, it bears a broad range of functions including DNA protection and participation in signalling pathways,” and that tau can be modified by a variety of cellular enzymes, which in turn broaden tau’s function and interaction spectrum (Borna et al., 2018). This means that, in tauopathies, multiple mechanisms can be modified at different levels in DNA conformation and expression, and that it is hard to discriminate which effect is disease-related, and which is not.

    In this study the only statistically significant alteration detected for transposable elements was in the transcriptional signature of HERV-Fc1 LTR. This could be relevant to correlate HERV-Fc1 to neurodegeneration, pending that transcripts driven by the LTR promoter are associated with some potentially neuropathogenic HERV-Fc1 ORFs, especially products of the env gene. It is known that the env proteins, which are the major proteins of the external envelope of retroviruses, have several properties that can be neuropathogenic. This has been shown for gp120 HIVenv, and, with respect to human endogenous retroviruses, only for the HERV-Wenv in multiple sclerosis, and HERV-Kenv in amyotrophic lateral sclerosis. In the latter two cases, transgenic mice containing the HERV-Wenv or HERV-Kenv genes developed a disease resembling, respectively, multiple sclerosis and amyotrophic lateral sclerosis.

    It is a pity that Guo and colleagues, having obtained the transcriptome profiling of the samples, did not look for HERV-Fc1env transcripts, and, if positive for this, to HERV-Fc1 env protein staining of the lesions of the brain tissues. These studies are easily done, and would strengthen the relationships between AD’s tauopathy and HERV-Fc1 involvement in neurodegeneration.  

    References:

    Borna H, Assadoulahei K, Riazi G, Harchegani AB, Shahriary A. Structure, Function and Interactions of Tau: Particular Focus on Potential Drug Targets for the Treatment of Tauopathies. CNS Neurol Disord Drug Targets. 2018;17(5):325-337. PubMed.

    View all comments by Antonina Dolei

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References

News Citations

  1. Do Sleeper Viruses Awaken in ALS?
  2. Location, Conformation, Decoration: Tau Biology Dazzles at AD/PD

Paper Citations

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Further Reading

Papers

  1. 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;13(3):e1006635. Epub 2017 Mar 16 PubMed.
  2. Küry P, Nath A, Créange A, Dolei A, Marche P, Gold J, Giovannoni G, Hartung HP, Perron H. Human Endogenous Retroviruses in Neurological Diseases. Trends Mol Med. 2018 Apr;24(4):379-394. Epub 2018 Mar 15 PubMed.
  3. Morandi E, Tanasescu R, Tarlinton RE, Constantinescu CS, Zhang W, Tench C, Gran B. The association between human endogenous retroviruses and multiple sclerosis: A systematic review and meta-analysis. PLoS One. 2017;12(2):e0172415. Epub 2017 Feb 16 PubMed.

Primary Papers

  1. Guo C, Jeong HH, Hsieh YC, Klein HU, Bennett DA, De Jager PL, Liu Z, Shulman JM. Tau Activates Transposable Elements in Alzheimer's Disease. Cell Rep. 2018 Jun 5;23(10):2874-2880. PubMed.

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