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.
- Tau Aggregates Awaken Genetic Relics in the Brain
- Jumping Genes Rampant in Tau Flies
- Neuroinflammation Field Grapples With Complexity at Keystone Symposia
- Genomic Double-Stranded RNA: Does C9ORF72 Cause Viral Mimetic Disease?
- Just Like Viruses, Tau Can Unleash Interferons
Research Models Citations
- 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.
- 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.
- Aberrant Heterochromatin, Gene Expression Inflame Old Cells
- Methylated RNA: A New Player in Tau Toxicity?
- Tau, Speckle Wrecker, Disrupts the Nuclear Home
- Invasion of the Microtubules: Mutant Tau Deforms Neuronal Nuclei
- Tau Stymies Transport Through Neuron’s Nucleus
- Genomic Double-Stranded RNA: Does C9ORF72 Cause Viral Mimetic Disease?
- Does ALS Gene Police RNA, Keep Strands From Entangling?
- 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.
- 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