. Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies. Nat Neurosci. 2018 Aug;21(8):1038-1048. Epub 2018 Jul 23 PubMed.

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  1. In this independent and insightful study combining investigations in fruit flies and human postmortem tissue, Dr. Frost’s team reports results that agree with, and significantly add to, our recent findings that tau pathology can modulate the activity of transposable elements in Alzheimer’s disease.

    This work addresses several questions that remained unresolved by our work. First, they used an available endogenous reporter to demonstrate additional evidence supporting new transposon insertions activated by tau. Second, Frost and colleagues enhance our understanding of relevant mechanisms, showing that besides chromatin relaxation, tau induced a reduction in piwi-interacting RNAs. Further, genetic manipulations that interfere with piRNAs enhance both TE expression and tau-induced neurotoxicity. Lastly, other interventions, including dietary restriction and pharmacologic treatment with the reverse transcriptase inhibitor 3TC, suppressed both TE activity and tau-induced neuronal death.

    While this work is highly suggestive, in my view, a key remaining question is whether TE activity truly directly mediates tau-induced neuronal injury or alternatively might yet represent a non-causal biomarker. This is a very challenging question to answer because most experimental manipulations evaluated, e.g. piRNA modulation, chromatin modulation, dietary restriction, and reverse transcriptase inhibitors, have widespread cellular and organismal impact beyond that of TE suppression.

    Regardless, I commend Dr. Frost and colleagues on this comprehensive study. It will surely inspire additional investigations of this important topic.

    View all comments by Joshua Shulman
  2. We have previously reported heterochromatin decondensation and global transcriptional upregulation, affecting both protein coding and non-oding genes, in Drosophila tauopathy models. Moreover, we believe that tau-induced heterochromatin decondensation is a leading factor that seeds neurotoxicity and disease pathogenesis.

    Sun et al. here report an increase in transcripts of the retrovirus group of transposable elements and transposable element dysregulation due to heterochromatin decondensation in tau expressing Drosophila brain cells. Based on the above and other experimental evidence, the authors propose that reverse transcriptase inhibitors could be used as a potential therapeutic strategy for the treatment of neurodegenerative tauopathies, including Alzheimer’s.

    Though transposon dysregulation has been noted earlier in some neurodegenerative disorders, this is an interesting finding and may have some future application potential. However, tau-induced chromatin remodeling and global transcriptional upregulation is likely to (in fact it does) dysregulate a large number of genes, especially genes located near heterochromatic regions. Hence, an increase in transcripts of the retrovirus group of transposable elements could be one or a few of them.

    Therefore, dysregulation of the retrotransposon genes and aberrant hopping of transposable elements in the genome of tau-expressing neuronal cells could be a fraction of more global happenings. Also, it is not clear if transposon dysregulation and heterochromatin decondensation form a vicious loop and regulate each other, or which appears first.

    Taken together, this is an interesting finding that shows a consequence of the global transcriptional upsurge. To me, it is the tip of the iceberg.

    View all comments by Surajit Sarkar

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