The human genome comes chock-full of transposable elements—ancient snippets of DNA that once hopped around the genome. Cells have evolved ways to silence these mobile motifs, but a new study suggests tau lets them loose, disrupting neuronal DNA and leading to a cell’s demise. Reporting July 23 in Nature Neuroscience, scientists led by Bess Frost, University of Texas Health San Antonio, find that human tau weakens epigenetic constraints and dampens the production of small RNAs that normally keep a lid on transposons. “Tau disrupts the two main cellular controls for silencing transposable elements in neurons,” said Frost. “We show that jumping transposable elements are deleterious to normal survival and causal for the disease process.” Tau may work the same way in people, Frost believes, as endogenous retroviruses similarly shake loose in tauopathy patients.
- Tau unfastens transposable elements (TE) from heterochromatin.
- Tau also depletes piRNAs that help degrade TE transcripts.
- Without either control, TE can jump and damage neurons.
“Until now, most of the evidence for the role of retrotransposons in neurodegenerative disease was in the context of ALS, multiple sclerosis, and macular degeneration,” said Joshua Dubnau, Stony Brook University School of Medicine, New York. “Now, this data suggests that loss of control of retrotransposons may be a hallmark of neurodegenerative disorders.” He cautioned that while activation of transposons may causally contribute to cellular toxicity and death, it could also be a consequence.
Transposable elements (TEs), also called transposons or “jumping genes,” are elements that can cut, copy, and paste themselves into different parts of the genome. Though TEs have persisted for millennia, most are transcriptionally silenced by constitutive heterochromatin. In other words, these genomic regions are so tightly wound on the chromosomes that they can’t jump. Any transcripts that do are caught by small RNAs called piwi-interacting RNAs. These bind and degrade TE transcripts before they can reintegrate in the genome.
The Model. Tau loosens heterochromatin and dampens piRNA production, leading to neuronal death. [Courtesy of Sun et al., Nature Neuroscience.]
Studies are finding that heterochromatin loosens with age, in cancer, and in TDP-43-mediated neurodegeneration, and this loosening accidentally releases the TEs (Li et al., 2013; Burns 2017; Li et al., 2012). Does tau free TEs, too? Frost’s group previously reported that tau relaxesd heterochromatin in flies, mice, and humans, and drove neuronal death in flies, but it was unclear if it also released transposable elements (Frost et al., 2014). Last month, another group of scientists led by Joshua Shulman, Baylor College of Medicine, Houston, reported that tau does release transposons, but these scientists didn’t know whether the transposons were reinserting back into the genome or driving neurodegeneration (Jun 2018 news).
First author Wenyan Sun and colleagues expressed, in Drosophila, either wild-type or mutated R406W human tau, which causes autosomal-dominant tauopathy. RNA sequencing showed that, compared with control flies, neurons in both transgenic flies started transcribing TEs by 10 days of age. Releasing more transposable elements caused neurons to reactivate their cell cycle, which had been demonstrated previously in tauopathy (Khurana et al., 2006).
Could piRNAs quash the problem? In the transgenic flies, most of the piRNAs that were examined were expressed below control levels, as was piwi, their central regulator. Even in flies without human tau, reducing piwi activated the cell cycle and killed neurons, suggesting that having fewer piRNAs contributed to neurodegeneration. On the flip side, overexpressing piwi dampened transposable elements in the presence of tau, and fewer neurons died.
Did the unleashed transcripts reinsert into other spots? To find out, the authors used a gypsy-TRAP reporter, which makes neurons glow green when a transposable element lands in a particular chromosomal hot spot for reinsertions. Sure enough, more neurons glowed green in 10-day-old flies that expressed mutant human tau than in controls.
The authors were able to prevent these transposable elements from reintegrating and killing neurons by inhibiting reverse transcriptase with the drug 3TC. This enzyme makes a DNA copy from an RNA template to form a double-stranded helix that can reinsert into the genome. Also known as lamivudine, 3TC is FDA-approved for the treatment of HIV and hepatitis B. Feeding flies daily with 3TC-laced food normalized transposon expression and rescued neurons.
To see if tau might also free TEs in human neurons, the authors examined postmortem tissue from patients with AD and progressive supranuclear palsy. In both types of tissue, TEs, especially human endogenous retroviruses, were upregulated, suggesting that tau destabilizes the human genome as well, the authors wrote.
Together, the results suggest that tau, both wild-type and mutant, relaxes heterochromatin so that transposons are transcribed, and reduces the piRNAs that would normally keep them in check. Frost suspects this is a universal process, where tau causes heterochromatin to lose its hold across the genome rather than specifically affecting transposable elements. While this model only expresses tau in neurons, the effect likely hits all cells.
“I think this is going to be a fairly common finding in neurodegenerative diseases,” said Chris Link, University of Colorado Boulder. “The authors make a convincing case in their models that tau disrupts the heterochomatin.” He said he would need to see more data regarding tau’s effect on the levels of piwi protein. Transposable elements have been caught jumping in other diseases, but Frost hasn’t seen loosening of heterochromatin in other models. It could be that something else mobilizes transposons, he said.
“The underlying theme behind diseases of aging might be dysregulation of the transposable elements and the ability to keep DNA shut down,” said Avindra Nath, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland. “When that control is lost, there is activation of oncogenes, transposable elements, and retroviruses that wreak havoc.” The role of transposable elements has yet to be fully explored in neurodegenerative diseases, he said. “This draws attention to a part of the human genome that probably plays an important role in their pathophysiology.”
In future work, Frost wants to test whether endogenous retroviruses are reinserting into the human genome. If so, that would suggest that tau drives genome disruption and neurodegeneration in people. In that case, a drug like 3TC could theoretically work in AD. Certain antiretrovirals are currently in clinical trials for amyotrophic lateral sclerosis, as TDP-43 also reportedly frees human endogenous retroviruses (Oct 2015 news).
Genome disruption and cell cycle activation may not be the only mechanisms of cell death. Transposable elements are by nature repetitive and so can form double-stranded RNA (dsRNA), the authors noted. The presence of dsRNA sets off alarm bells in the innate immune system, which could contribute to neuroinflammation, they wrote.
Link noted that relaxed heterochromatin likely releases other repetitive elements in the genome, which might contribute to an inflammatory response. A recent paper spotted more transcripts for viral response genes in AD than control brain (Jun 2018 news). DsRNA is a bridge between these two papers, Link said, as it crops up with both endogenous and infectious viruses.—Gwyneth Dickey Zakaib
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