Scientists at UT Health San Antonio have linked unwanted activation of transposable elements, or "jumping genes," with nerve cell death in neurodegenerative tauopathies such as Alzheimer’s disease. Their studies in fruit flies found that toxic tau protein deposition that is characteristic of tauopathies is associated with the disruption of epigenetic mechanisms that control the expression of transposable genetic elements, and that this dysregulation links with the death of neurons.
Led by Bess Frost, Ph.D., assistant professor of cell systems and anatomy, University of Texas Health, San Antonio, the researchers also showed that treating the fruit fly model using lamivudine, a reverse transcriptase inhibitor drug that is approved for treating HIV and hepatitis B, could effectively halt transposable element dysregulation and reduce tau-induced neurotoxicity in the flies.
The team separately identified upregulated expression of transposable elements in postmortem brain tissue samples from patients with two types of tauopathy, implying that similar mechanisms may be at work in some human neurodegenerative disorders.
"The toxic tau can be present, but if we give this drug and it blocks the transposable element activity, it's enough to decrease the amount of brain cells that are dying in the fly model," comments Dr. Frost, who is a member of the Barshop and Biggs Institutes at UT Health San Antonio. "We know that these genes are copying themselves at higher levels in the tauopathy fly model. And we know we can stop that from happening by giving them this drug."
Reporting their findings in Nature Neuroscience, the UT Health San Antonio team and collaborators concluded, "On the basis of the data presented here, reverse transcriptase inhibitors have significant potential as a therapeutic strategy for the treatment of neurodegenerative tauopathies, including Alzheimer’s disease.” Their published paper is titled, “Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies.”
Transposable elements are DNA sequences that can copy themselves and move from one place in the genome to another. They comprise about 45% of the human genome, Dr. Frost and colleagues write. There are different categories of transposable elements. Class I retrotransposons are structurally similar to retroviruses, and require an RNA intermediate and the activity of a reverse transcriptase to transcribe the RNA back into DNA. Class II DNA transposons don’t use an RNA intermediate, they can effectively copy themselves somewhere else in the genome via a "cut and paste" mechanism.
Organisms have developed control mechanisms that limit potentially harmful transposable element activity, the researchers explained. “Many transposable elements are embedded within highly condensed constitutive heterochromatin and are thus epigenetically silenced. In addition, transposable element transcripts are the targets of a well-conserved pathway involving piRNAs [piwi-interacting RNAs], small regulatory RNAs that bind to transposable element transcripts and mediate their degradation.”
Transposable element activity has been implicated in aging and in some diseases such as cancer, but to what degree transposons are causally linked with disease isn’t known. The UT Health San Antonio team reported that they had previously identified tau-induced decondensation of constitutive heterochromatin as “a key event that mediates neuronal death in tauopathy," and reasoned that this might cause “epigenetic de-silencing” of transposable elements, effectively allowing them to replicate.
To investigate this further they turned to Drosophila melanogaster models of tauopathy, which demonstrate progressive, age-associated neuronal death, together with cellular and molecular features that are characteristic of human Alzheimer’s disease and associated tauopathies.
Their studies showed that the fruit fly models exhibited altered levels of transposable element transcripts in response to increased levels of tau protein, and that toxic tau protein accumulation resulted in loss of piRNA-mediated transposable element silencing, which was causally linked to neuronal cell death. “…tau-induced reduction of piwi and piRNAs is a major contributor to the transposable element expression profile in brains of tau transgenic Drosophila,” they write.
Even in the absence of tau protein, piwi knockdown was enough to induce neuronal death in the flies. Conversely, overexpressing piwi led to significantly reduced levels of transposable element transcripts. The authors suggest that their collective data indicated that “tau-induced piwi reduction depletes piRNAs, which significantly increases transposable element transcripts and causally contributes to tau-induced neurotoxicity.”
Further experiments showed that genetically promoting heterochromatin relaxation also resulted in increased levels of most of the transposable element transcripts that were found to be increased in the tau transgenic Drosophila. “In the context of our previous report identifying tau-induced heterochromatin decondensation as a central mediator of neurotoxicity in tauopathy, these data suggest that tau-induced heterochromatin decondensation contributes to transposable element dysregulation in brains of tau transgenic Drosophila,” the authors write. “Mechanistically, we find that heterochromatin decondensation and reduction of piwi and piRNAs drive transposable element dysregulation in tauopathy."
Dietary restriction is known to extend lifespan in invertebrates, but also to reduce age-related transposable element mobilization in the Drosophila fat body, a tissue that plays a key role in energy storage. The researchers next showed that a 66% dietary restriction in the Drosophila model reduced tau-induced transposable element activation in neurons, demonstrating that it is at least possible to suppress tau-induced transposable element dysregulation and neuronal death.
Retrotransposons encode retrovirus-like elements that are required for this type of transposable element to replicate itself and insert the new copy into the genome. With this in mind, the researchers then tested the antiretroviral drug, lamivudine, in the fruit fly model of tauopathy. They found that the reverse transcriptase inhibitor significantly and dose-dependently reduced both tau-induced neuronal death and the telltale locomotor deficits in the flies. The authors claim that their combined results provide “further evidence that transposable element dysregulation causes the disease process in tauopathy and is responsive to environmental and pharmacological inhibition.”
When they next examined postmortem brain tissue from patients with either Alzheimer’s disease or another tauopathy, progressive supranuclear palsy, they found that both disorders were associated with increased levels of transcripts of an endogenous retrovirus class of transposable elements.
“Taken together, our data identify heterochromatin decondensation, piwi and piRNA depletion and consequent transposable element dysregulation as a pharmacologically targetable, mechanistic driver of neurodegeneration in tauopathy,” the authors concluded. “… we show that that suppression of transposable element mobilization and resulting neurodegeneration can be achieved by environmental and pharmacological intervention."