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).
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.
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
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