Does Double-Stranded RNA From Jumping Genes Mediate Tau Toxicity?

How does aggregated tau wreak damage? In the January 6 Science Advances, researchers led by Bess Frost at the University of Texas Health San Antonio make a case for tau unleashing double-stranded RNA. In fruit fly brain, mutant tau opened up chromatin, allowing transcription from retrotransposons and creating dsRNA. This duplex triggered viral defense mechanisms, sparking neuroinflammation and neuronal damage. Conversely, enzymatically chopping up dsRNA quieted inflammation and protected neurons. The scientists detected more dsRNA in the brains of people who died with Alzheimer’s disease or progressive supranuclear palsy than in healthy controls, suggesting the transcripts could be a factor in human tauopathy. If so, muting retrotransposons or mopping up dsRNA might ameliorate disease, Frost noted.

  • In fruit flies, mutant tau activates retrotransposons, boosting transcription of dsRNA.
  • Accumulation of dsRNA in glia kicks off inflammation and neurodegeneration.
  • In human tauopathies, dsRNA builds up in astrocytes.

“This is very exciting work from the Frost Lab,” said Mahmoud Maina at the University of Sussex, Brighton, U.K. He noted that the data shed new light on the mechanisms underlying tau toxicity. Samuel Beck at the MDI Biological Laboratory in Bar Harbor, Maine, agreed that the findings may point toward new treatments. “This [paper] indicates that tau-mediated dsRNA production plays a fundamental role in neurodegeneration, providing an important therapeutic strategy against tauopathies,” he wrote to Alzforum (full comments below).

The Making of dsRNA. Retrotransposons (yellow) form double-stranded RNA (aqua) by two different pathways (arrows); this dsRNA can be made into cDNA (blue) that disrupts the genome, or it can trigger an immune response. [Courtesy of Ochoa et al., Science Advances/AAAS].

Frost and others had previously implicated tau aggregates in rousing transposons, which are normally kept tightly packed away in quiescent sections of chromatin to prevent them from “jumping” to new locations in the genome and disrupting DNA (Jun 2018 news; Jul 2018 news). How does tau do this? Previously, Frost reported that mutant tau in the cytosol stiffened the actin cytoskeleton, which in turn put pressure on the nucleoskeleton, disrupting the condensed heterochromatin anchored there. The heterochromatin then opened up, exposing retrotransposons and causing neurodegeneration (Frost et al., 2014; Frost et al., 2016). 

In the new work, Frost dug deeper into exactly how retrotransposons cause havoc. These ancient viral genes frequently produce dsRNA, either via bidirectional transcription and the subsequent pairing up of complementary strands, or because repeated, inverted genetic sequences allow the transcripts to fold over and pair with themselves.

To see if these aberrant nucleic acids might be the culprit, first author Elizabeth Ochoa measured dsRNA in the brains of adult Drosophila that express pathogenic R406W tau in their neurons. The brains contained about one-third more dsRNA than wild-type fly brains do, and, as expected, the dsRNA included several known retrotransposons. Surprisingly, however, dsRNA accumulated in a type of glia, not neurons. “That was a really unexpected finding,” Frost told Alzforum. These glia support neuronal health, similar to astrocytes in human brain.

Because retroviruses carry dsRNA, immune systems have evolved to respond to it. The authors detected activation of all the major immune pathways in the brains of these flies: Toll, immune deficiency (IMD), and Jak/STAT. The Toll pathway recognizes invasive fungi and bacteria, IMD turns on antimicrobial defense mechanisms, and Jak/STAT responds to interleukin signaling. Would getting rid of dsRNA help? Crossing the tauopathy model with flies that overexpressed the ribonuclease Dicer-2 in neurons lowered dsRNA load, cooled neuroinflammation back to control levels, and cut neuronal death almost in half.

Frost believes that neuronal Dicer-2 suppressing dsRNA in flies implies that these transcripts form in neurons but are secreted, and taken up by glia. She does not know which cell type might contribute most to the inflammatory and degenerative effects, but plans to investigate that with co-culture experiments and transgenic animal models.

Do these findings apply to mammals? The authors measured a fourfold accumulation of dsRNA in astrocytes of rTg4510 tauopathy mice, as well as massive upregulation of the dsRNA sensor MDA5. Likewise, in frontal cortex samples from 17 AD and eight PSP brains, dsRNA was up about threefold compared to the levels in eight control brains. MDA5 was up about twofold. Again, dsRNA accumulated in astrocytes, not neurons.

Ben Wolozin at Boston University noted that astrocytes can respond dramatically to neuronal pathology. “The finding that [dsRNA] occurs in astrocytes raises many important mechanistic questions that demand exploration,” he wrote to Alzforum. He was impressed that dsRNA was elevated already in brains at Braak stage 2, early in disease.

Robert Rissman at the University of California, San Diego, believes the data are convincing in the fly model. More functional work is needed to nail down neurotoxic pathways in mammals, for example by knocking down MDA5 or other elements of the dsRNA response. Disease mechanisms may be different in humans, due to their longer lives and their expression of additional tau isoforms, Rissman noted.

Other work has hinted at a role for dsRNA in neurodegeneration, including in diseases such as amyotrophic lateral sclerosis and frontotemporal dementia (Feb 2015 conference news; Jul 2021 news). Nor is it just RNA; some studies implicate dsDNA leaking out of mitochondria in setting off the immune system via the cGAS-STING sensor (Apr 2022 conference news).

In the January 9 Nature Aging, researchers led by Zhen Zhao at the University of Southern California, Los Angeles, and Jianxiong Zeng at the Chinese Academy of Sciences, Kunming, reported that cGAS-STING is elevated in AD brain and in mouse models. In 5XFAD mice, knocking out cGAS prevented amyloid accumulation, neuroinflammation, and memory loss, suggesting a role for this immune pathway in pathology.

Meanwhile, Frost is testing the potential of the antiretroviral medication lamivudine in a small pilot study of 12 people with early AD. First developed for HIV, this drug suppresses reverse transcription of RNA into DNA, potentially preventing genetic damage in people with activated retrotransposons. Frost noted that this approach is unlikely to tame accumulation of dsRNA and the subsequent inflammation. For that, researchers might need to boost RNA clearance mechanisms, or prevent the opening of heterochromatin in the first place, she suggested.

Others are testing antiviral drugs as well, with trials of the HIV medication TPN-101 underway for both ALS/FTD and the tauopathy progressive supranuclear palsy.—Madolyn Bowman Rogers

Comments

    • User Profile Image Samuel Beck
      Boston University School of Medicine
    • Posted:

    This exciting study identifies a new and critical player of tau-mediated neurodegeneration, i.e., the production of retrotransposon-derived dsRNA that, in turn, plays a causal role in neuroinflammation. Their results demonstrate that tau-mediated dsRNA production is broadly conserved among humans, mice, and even flies, and that its inhibition can suppress neuroinflammation. This indicates that tau-mediated dsRNA production plays a fundamental role in neurodegeneration, providing an important therapeutic strategy against tauopathies.

    View all comments by Samuel Beck

  2. This very exciting work from the Frost lab builds on their previous work on the role of tau in driving neurodegeneration through chromatin remodeling. Now, they report that dsRNA is elevated in astrocytes of postmortem brain tissue from patients with progressive supranuclear palsy and Alzheimer's disease, in the brains of tau transgenic mice, and in the Drosophila model of tauopathy. In Drosophila, they identified specific tau-induced retrotransposons that form dsRNA, and they found that pathogenic tau and heterochromatin de-condensation causally drive dsRNA-mediated neuroinflammation. Overall, the study suggests that pathogenic tau-induced heterochromatin de-condensation and retrotransposon activation cause an elevation of inflammatory, transposable element-derived dsRNA in the adult brain, which may contribute to the neuronal degeneration seen in tauopathies.

    This is clearly an exciting study that continues to imply a role for tau beyond the microtubules in tauopathies. The use of both human brain tissue samples and animal models (Drosophila and mice) enhances the generality of the findings. However, it is important to understand that while the study provides strong evidence for links between tau-induced heterochromatin de-condensation, retrotransposon activation, and neuroinflammation, further research will be needed to understand whether these changes apply in other tauopathy models and to fully understand the underlying molecular mechanisms. For example, we don’t currently know whether these changes are due to a direct impact of tau on the chromatin and if yes, which form of tau. Phosphotau? Tau oligomers?

    Foundational work from Lester Binder’s group and more recent work from others in the field, especially Luc Buée and Marie-Christine Galas groups, has identified that tau localizes and binds to the DNA especially when non-phosphorylated. Accordingly, our ongoing work has further identified that this non-phosphorylated tau is important for nucleolar function. So, the question that has yet to be answered is whether pathogenic tau impacts the normal nuclear or DNA-binding function of non-phosphorylated tau that results in the changes observed, or if pathogenic tau directly binds the chromatin to cause these changes. These are questions that I hope future research will address.

    Moreover, previous studies on the nuclear role of tau have mostly focused on neuronal cells, although tau has been found in many cell types including those found outside the nervous system. This work suggests that nuclear tau may play a functional and pathogenic role in those other cell types, such as astrocytes. This nicely ties in with recent studies in the field that suggest non-neuronal mechanisms driving neurodegeneration in tauopathies.

    In conclusion, the study provides important new insights into the mechanisms of tau toxicity in tauopathies and provides strong justification for studying other functions of tau that are critical for us to better understand and treat tauopathies.

    View all comments by Mahmoud Bukar Maina

  3. This is a really interesting paper! I think there is a fair bit of evidence from numerous groups that transposable elements increase in neurodegenerative diseases. Josh Dubnau at Cold Spring Harbor Labs showed this in a fly ALS model. Josh Shulman at Baylor showed this informatically in humans. Frost’s article is nicely done and shows elevation of dsRNA in human brain and probes mechanisms using the fly. Three things are particularly striking to me:

    1. The increase in dsRNA occurs in mild cases, with Braak II/III. That is quite mild for the striking molecular pathology.
    2. Bess’ group sees dsRNA in PSP, so we know the culprit is tau, not Ab.
    3. In humans and mice, the increased dsRNA occurs in astrocytes. This is surprising because tau generally accumulates in neurons. Hence, it would seem hard to argue that tau directly causes the accumulation; instead the results suggests that the astrocytes must respond to tau accumulation in the neurons early on. Such intimate interactions between neurons and astrocytes are known. We have a nice paper in Nature Communications in which we report a really nice induction of pathology in human iPSC-derived assembloids (Ricnker et al., 2022). This article has a lot of information in it, but the point relevant to Frost’s paper is that we seed neurons in a two-dimensional culture stage, then a day later combine them with astrocytes to make three-dimensional assembloids. Although the astrocytes never see the tau, scRNAseq shows that nevertheless they immediately and dramatically respond to the neuronal pathology (Fig. 4 and 5 of our paper). All of this is to say that it is very clear that astrocytes respond quickly and deeply to neuronal pathology.

    I am not convinced that tau is directly causing the transposon activation in astrocytes, because the tau accumulates mostly in the neurons, with little (depending on the type of tauopathy) accumulating in astrocytes. Nevertheless, the demonstration of massive changes in transposon reactivity adds to the literature, and the finding that it occurs in astrocytes raises many important mechanistic questions that demand exploration. The transposons might also ultimately prove to be a very useful biomarker, although this was not addressed.

    References:

    Rickner HD, Jiang L, Hong R, O'Neill NK, Mojica CA, Snyder BJ, Zhang L, Shaw D, Medalla M, Wolozin B, Cheng CS. Single cell transcriptomic profiling of a neuron-astrocyte assembloid tauopathy model. Nat Commun. 2022 Oct 21;13(1):6275. PubMed.

    View all comments by Benjamin Wolozin
    • User Profile Image Robert Rissman
      University of Southern California, San Diego
    • Posted:

    This is an interesting paper. Just to note, the work in AD and PSP tissue, as well as the tau mice, is observational—they see evidence of change in dsRNA and its machinery at different stages of disease, but no further work is pursued. So many things are messed up in AD brains and the brains of mice with advanced pathology that it’s sometimes hard to get excited about such observations.

    Still, the findings suggest a mechanistic link between retrotransposon activity that produces dsRNA, and "pathogenic" tau that drives neurodegeneration and inflammation. All of this can be modulated by the helicase MDA5. The results are very interesting and exciting, but additional testing in mouse models with, perhaps, siRNA or knockout of aspects of the dsRNA system, or of MDA5, is needed to really appreciate the therapeutic potential of the work. Working with flies is useful, but limited in many regards, including their survival time. Notably, flies don't have astrocytes, which are important cells of interest here. Repeating/testing their hypothesis in mouse models, longitudinally, and including behavioral testing as well as anatomical and biochemical analyses, would really strengthen the therapeutic potential of targeting the dsRNA system or retrotransposons. 

    So, is this a plausible way that tau exerts neurotox? Maybe. The data presented are very convincing in the fly model. However, there may be many ways that tau executes its toxic effects in the brain. Also, whether this extends to other species, such as mouse models of human disease, is unknown due to the "acute" nature of disease development in flies and their limited lifespan, as mentioned above. The mechanistic underpinnings of disease in mammals may also be different. In addition, in the case of AD, there is Aβ accumulation early that may be involved in tau progression. That is not considered here, because the models are tau only. 

    In terms of additional observational work, it would be interesting to see how dsRNA, MDA5, and other intermediates change over time in Aβ mouse models, given that some phospho-tau or other "pathogenic" tau species develop to limited degrees in flies, which only express 4R tau (as does the mouse model the authors used). In AD, 3R tau species are also involved in disease and cause toxic effects. I wonder if pathogenic 3R tau species can also induce the effects seen here in the 4R models.

    View all comments by Robert Rissman

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References

News Citations

  1. Tau Aggregates Awaken Genetic Relics in the Brain
  2. Jumping Genes Rampant in Tau Flies
  3. Neuroinflammation Field Grapples With Complexity at Keystone Symposia
  4. Genomic Double-Stranded RNA: Does C9ORF72 Cause Viral Mimetic Disease?
  5. Just Like Viruses, Tau Can Unleash Interferons

Mutations Citations

  1. MAPT R406W

Research Models Citations

  1. rTg(tauP301L)4510
  2. 5xFAD (C57BL6)

Therapeutics Citations

  1. TPN-101

Paper Citations

  1. Frost B, Hemberg M, Lewis J, Feany MB. Tau promotes neurodegeneration through global chromatin relaxation. Nat Neurosci. 2014 Mar;17(3):357-66. Epub 2014 Jan 26 PubMed.
  2. Frost B, Bardai FH, Feany MB. Lamin Dysfunction Mediates Neurodegeneration in Tauopathies. Curr Biol. 2016 Jan 11;26(1):129-36. Epub 2015 Dec 24 PubMed.

External Citations

  1. pilot study
  2. ALS/FTD
  3. progressive supranuclear palsy

Further Reading

Primary Papers

  1. Ochoa E, Ramirez P, Gonzalez E, De Mange J, Ray WJ, Bieniek KF, Frost B. Pathogenic tau-induced transposable element-derived dsRNA drives neuroinflammation. Sci Adv. 2023 Jan 6;9(1):eabq5423. PubMed.
  2. Xie X, Ma G, Li X, Zhao J, Zhao Z, Zeng J. Activation of innate immune cGAS-STING pathway contributes to Alzheimer’s pathogenesis in 5×FAD mice. Nat Aging 9 January 2023 Nature Aging

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