1. Neuroscience

Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription

  1. Rui Gao
  2. Anirban Chakraborty
  3. Charlene Geater
  4. Subrata Pradhan
  5. Kara L Gordon
  6. Jeffrey Snowden
  7. Subo Yuan
  8. Audrey S Dickey
  9. Sanjeev Choudhary
  10. Tetsuo Ashizawa
  11. Lisa M Ellerby
  12. Albert R La Spada
  13. Leslie M Thompson
  14. Tapas K Hazra
  15. Partha S Sarkar  Is a corresponding author
  1. University of Texas Medical Branch, United States
  2. University of California, Irvine, United States
  3. Duke University School of Medicine, United States
  4. Sam Houston State University, United States
  5. Houston Methodist Research Institute, United States
  6. Buck Institute for Research on Aging, United States
https://doi.org/10.7554/eLife.42988
Share this article
Cite this article
  1. Rui Gao
  2. Anirban Chakraborty
  3. Charlene Geater
  4. Subrata Pradhan
  5. Kara L Gordon
  6. Jeffrey Snowden
  7. Subo Yuan
  8. Audrey S Dickey
  9. Sanjeev Choudhary
  10. Tetsuo Ashizawa
  11. Lisa M Ellerby
  12. Albert R La Spada
  13. Leslie M Thompson
  14. Tapas K Hazra
  15. Partha S Sarkar
(2019)
Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription
eLife 8:e42988.
https://doi.org/10.7554/eLife.42988
  2. Download BibTeX
  3. Download .RIS

Abstract

How huntingtin (HTT) triggers neurotoxicity in Huntington's disease (HD) remains unclear. We report that HTT forms a transcription-coupled DNA repair (TCR) complex with RNA polymerase II subunit A (POLR2A), ataxin-3, the DNA repair enzyme polynucleotide-kinase-3'-phosphatase (PNKP), and cyclic AMP-response element-binding (CREB) protein (CBP). This complex senses and facilitates DNA damage repair during transcriptional elongation, but its functional integrity is impaired by mutant HTT. Abrogated PNKP activity results in persistent DNA break accumulation, preferentially in actively transcribed genes, and aberrant activation of DNA damage-response ataxia telangiectasia-mutated (ATM) signaling in HD transgenic mouse and cell models. A concomitant decrease in Ataxin-3 activity facilitates CBP ubiquitination and degradation, adversely impacting transcription and DNA repair. Increasing PNKP activity in mutant cells improves genome integrity and cell survival. These findings suggest a potential molecular mechanism of how mutant HTT activates DNA damage-response pro-degenerative pathways and impairs transcription, triggering neurotoxicity and functional decline in HD.

Data availability

All data generated are included in the manuscript and supporting files.

Article and author information

Author details

  1. Rui Gao

    Department of Neurology, University of Texas Medical Branch, Galveston, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Anirban Chakraborty

    Department of Internal Medicine, University of Texas Medical Branch, Galveston, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Charlene Geater

    Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Subrata Pradhan

    Department of Neurology, University of Texas Medical Branch, Galveston, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Kara L Gordon

    Department of Neurology, Duke University School of Medicine, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Jeffrey Snowden

    Department of Neurology, University of Texas Medical Branch, Galveston, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Subo Yuan

    Department of Neuroscience, University of Texas Medical Branch, Galveston, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Audrey S Dickey

    Department of Neurology, Duke University School of Medicine, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Sanjeev Choudhary

    Department of Biochemistry, Cell Biology and Genetics, Sam Houston State University, Huntsville, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Tetsuo Ashizawa

    Department of Neurology, Houston Methodist Research Institute, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Lisa M Ellerby

    Buck Institute for Research on Aging, Novato, United States
    Competing interests
    The authors declare that no competing interests exist.

  12. Albert R La Spada

    Department of Neurology, Duke University School of Medicine, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6151-2964

  13. Leslie M Thompson

    Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.

  14. Tapas K Hazra

    Department of Internal Medicine, University of Texas Medical Branch, Galveston, United States
    Competing interests
    The authors declare that no competing interests exist.

  15. Partha S Sarkar

    Department of Neurology, University of Texas Medical Branch, Galveston, United States
    For correspondence
    pssarkar@utmb.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2885-8100

Funding

NIH Office of the Director (NSO79541-01)

  • Tapas K Hazra
  • Partha S Sarkar

NIH Office of the Director (NS073976)

  • Tapas K Hazra

Hereditary Disease Foundation (Postdoctoral Fellowship)

  • Charlene Geater

Mitchel Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX (Developmental Grant)

  • Partha S Sarkar

NIH Office of the Director (EY026089-01A1)

  • Partha S Sarkar

NIH Office of the Director (NS100529)

  • Lisa M Ellerby

NIH Office of the Director (AG033082)

  • Albert R La Spada

NIH Office of the Director (NS065874)

  • Albert R La Spada

NIH Office of the Director (NS089076)

  • Leslie M Thompson

NIH Office of the Director (NS090390)

  • Leslie M Thompson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All procedures involving animals were in accordance with the National Institutes of Health Guide for the care and use of Laboratory Animals, and approved by the Institutional Animal Care and Use Committee of University of California Irivine (protocol #: AUP-18-155); and Duke University (protocol #: A225-17-09).

Reviewing Editor

  1. Harry T Orr, University of Minnesota, United States

Version history

  1. Received: October 19, 2018
  2. Accepted: April 16, 2019
  3. Accepted Manuscript published: April 17, 2019 (version 1)
  4. Version of Record published: May 21, 2019 (version 2)

Copyright

© 2019, Gao et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,689
    Page views
  • 791
    Downloads
  • 65
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Rui Gao
  2. Anirban Chakraborty
  3. Charlene Geater
  4. Subrata Pradhan
  5. Kara L Gordon
  6. Jeffrey Snowden
  7. Subo Yuan
  8. Audrey S Dickey
  9. Sanjeev Choudhary
  10. Tetsuo Ashizawa
  11. Lisa M Ellerby
  12. Albert R La Spada
  13. Leslie M Thompson
  14. Tapas K Hazra
  15. Partha S Sarkar
(2019)
Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription
eLife 8:e42988.
https://doi.org/10.7554/eLife.42988

Categories and tags

Research organism

Further reading

    1. Evolutionary Biology
    2. Neuroscience

    Diversity and evolution of cerebellar folding in mammals

    Katja Heuer, Nicolas Traut ... Roberto Toro
    Research Article

    The process of brain folding is thought to play an important role in the development and organisation of the cerebrum and the cerebellum. The study of cerebellar folding is challenging due to the small size and abundance of its folia. In consequence, little is known about its anatomical diversity and evolution. We constituted an open collection of histological data from 56 mammalian species and manually segmented the cerebrum and the cerebellum. We developed methods to measure the geometry of cerebellar folia and to estimate the thickness of the molecular layer. We used phylogenetic comparative methods to study the diversity and evolution of cerebellar folding and its relationship with the anatomy of the cerebrum. Our results show that the evolution of cerebellar and cerebral anatomy follows a stabilising selection process. We observed 2 groups of phenotypes changing concertedly through evolution: a group of 'diverse' phenotypes - varying over several orders of magnitude together with body size, and a group of 'stable' phenotypes varying over less than 1 order of magnitude across species. Our analyses confirmed the strong correlation between cerebral and cerebellar volumes across species, and showed in addition that large cerebella are disproportionately more folded than smaller ones. Compared with the extreme variations in cerebellar surface area, folial anatomy and molecular layer thickness varied only slightly, showing a much smaller increase in the larger cerebella. We discuss how these findings could provide new insights into the diversity and evolution of cerebellar folding, the mechanisms of cerebellar and cerebral folding, and their potential influence on the organisation of the brain across species.

    1. Neuroscience

    Hunger- and thirst-sensing neurons modulate a neuroendocrine network to coordinate sugar and water ingestion

    Amanda J González Segarra, Gina Pontes ... Kristin Scott
    Research Article

    Consumption of food and water is tightly regulated by the nervous system to maintain internal nutrient homeostasis. Although generally considered independently, interactions between hunger and thirst drives are important to coordinate competing needs. In Drosophila, four neurons called the interoceptive subesophageal zone neurons (ISNs) respond to intrinsic hunger and thirst signals to oppositely regulate sucrose and water ingestion. Here, we investigate the neural circuit downstream of the ISNs to examine how ingestion is regulated based on internal needs. Utilizing the recently available fly brain connectome, we find that the ISNs synapse with a novel cell-type bilateral T-shaped neuron (BiT) that projects to neuroendocrine centers. In vivo neural manipulations revealed that BiT oppositely regulates sugar and water ingestion. Neuroendocrine cells downstream of ISNs include several peptide-releasing and peptide-sensing neurons, including insulin producing cells (IPCs), crustacean cardioactive peptide (CCAP) neurons, and CCHamide-2 receptor isoform RA (CCHa2R-RA) neurons. These neurons contribute differentially to ingestion of sugar and water, with IPCs and CCAP neurons oppositely regulating sugar and water ingestion, and CCHa2R-RA neurons modulating only water ingestion. Thus, the decision to consume sugar or water occurs via regulation of a broad peptidergic network that integrates internal signals of nutritional state to generate nutrient-specific ingestion.

    1. Neuroscience

    Dynamic top-down biasing implements rapid adaptive changes to individual movements

    Lucas Y Tian, Timothy L Warren ... Michael S Brainard
    Research Article

    Complex behaviors depend on the coordinated activity of neural ensembles in interconnected brain areas. The behavioral function of such coordination, often measured as co-fluctuations in neural activity across areas, is poorly understood. One hypothesis is that rapidly varying co-fluctuations may be a signature of moment-by-moment task-relevant influences of one area on another. We tested this possibility for error-corrective adaptation of birdsong, a form of motor learning which has been hypothesized to depend on the top-down influence of a higher-order area, LMAN (lateral magnocellular nucleus of the anterior nidopallium), in shaping moment-by-moment output from a primary motor area, RA (robust nucleus of the arcopallium). In paired recordings of LMAN and RA in singing birds, we discovered a neural signature of a top-down influence of LMAN on RA, quantified as an LMAN-leading co-fluctuation in activity between these areas. During learning, this co-fluctuation strengthened in a premotor temporal window linked to the specific movement, sequential context, and acoustic modification associated with learning. Moreover, transient perturbation of LMAN activity specifically within this premotor window caused rapid occlusion of pitch modifications, consistent with LMAN conveying a temporally localized motor-biasing signal. Combined, our results reveal a dynamic top-down influence of LMAN on RA that varies on the rapid timescale of individual movements and is flexibly linked to contexts associated with learning. This finding indicates that inter-area co-fluctuations can be a signature of dynamic top-down influences that support complex behavior and its adaptation.