Evidence map›Paper›PMID 40777236›Full record

ArticlebioRxiv : the preprint server for biology2025

Huntingtin preserves mitochondrial genome integrity in neurons, which is impaired in Huntington's disease.

Subrata Pradhan, Sagar Gaikwad, Chi-Lin Tsai, Charlene Smith, Nan Zhang, Keegan Bush, Anirban Chakraborty, Subo Yuan, Sanjeev Choudhary, C Dirk Keene and 9 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

19 authors.

Subrata PradhanDepartment of Neurobiology, University of Texas Medical Branch, Galveston, Texas, USA.
Sagar GaikwadDepartment of Neurobiology, University of Texas Medical Branch, Galveston, Texas, USA.ORCID 0000-0003-2040-1357
Chi-Lin TsaiDepartment of Molecular & Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Charlene SmithDepartment of Psychiatry and Human Behavior, Department of Neurobiology and Behavior, and the Sue and Bill Gross Stem-Cell Center, University of California, Irvine, USA.
Nan ZhangDepartment of Neurology, Houston Methodist Research Institute, Houston, Texas, USA.
Keegan BushDepartment of Neurobiology, University of Texas Medical Branch, Galveston, Texas, USA.
Anirban ChakrabortyDepartment of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA.
Subo YuanDepartment of Neurobiology, University of Texas Medical Branch, Galveston, Texas, USA.
Sanjeev ChoudharyDepartment of Biochemistry, University of Northern Colorado, Greeley, Colorado, USA.
C Dirk KeeneDepartment of Laboratory Medicine and Pathology, University of Washington, Seattle, USA.
Lisa M EllerbyBuck Institute for Research on Aging, Novato, California, USA.
Tapas K HazraDepartment of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA.
Albert R La SpadaDepartments of Pathology & Laboratory Medicine, Neurology, and Biological Chemistry, and the UCI Institute for Neurotherapeutics, University of California, Irvine, USA.
Yogesh P WairkarDepartment of Neurobiology, University of Texas Medical Branch, Galveston, Texas, USA.
Tatsuo AshizawaDepartment of Neurology, Houston Methodist Research Institute, Houston, Texas, USA.
John A TainerDepartment of Molecular & Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Tej K PanditaCenter for Genomics and Precision Medicine, Texas A&M, Houston, TX 77030.
Leslie M ThompsonDepartment of Psychiatry and Human Behavior, Department of Neurobiology and Behavior, and the Sue and Bill Gross Stem-Cell Center, University of California, Irvine, USA.
Partha S SarkarDepartment of Neurobiology, University of Texas Medical Branch, Galveston, Texas, USA.

Funding

Transcription-Coupled & Replication-Associated Excision RepairP01CA092584 · NCI · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · PI John A. Tainer · 2001 to 2026
$89.6M
University of Washington Alzheimer's Disease Research CenterP30AG066509 · NIA · UNIVERSITY OF WASHINGTON · PI Amanda D. Boyd · 2020 to 2026
$29.0M
Molecular Mechanisms of Pathogenesis in Huntington’s diseaseR35NS116872 · NINDS · UNIVERSITY OF CALIFORNIA-IRVINE · PI Leslie Michels Thompson · 2020 to 2026
$8.5M
Mesoscale and Nanoscale Technologies Integrated by Structures for DNA Repair Complexes (MANTIS-DRC)R35CA220430 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI John A. Tainer · 2018 to 2026
$7.6M
Identifying Factors Regulating Medium Spiny Neuron Differentiation or Maintenance as Therapeutic Targets for Huntington's Disease using Induced Pluripotent Stem CellsR01NS100529 · NINDS · BUCK INSTITUTE FOR RESEARCH ON AGING · PI Lisa M Ellerby · 2016 to 2026
$5.6M
The PPAR-delta pathway in neural function and Huntington's disease neuropathologyR01NS065874 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI LA SPADA, ALBERT R · 2010 to 2020
$4.0M
Molecular genetic regulation of autophagy in health and neurodegenerative diseaseR01AG033082 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI LA SPADA, ALBERT R · 2009 to 2019
$4.0M
Supplement to Pathogenesis of HIV-associated sensory neuropathyR01NS122571 · NINDS · UNIVERSITY OF TEXAS MED BR GALVESTON · PI YUAN, SUBO · 2021 to 2025
$2.1M
Neuroregulatory Mechanisms of PIAS1 and Implications for Huntington's DiseaseR01NS090390 · NINDS · UNIVERSITY OF CALIFORNIA-IRVINE · PI DAVIDSON, BEVERLY L., THOMPSON, LESLIE MICHELS · 2015 to 2018
$1.8M
Pathogenic Role of DNA-Damage Response Pathway in the Diabetic RetinaR01EY026089 · NEI · UNIVERSITY OF TEXAS MED BR GALVESTON · PI SARKAR, PARTHA S · 2016 to 2019
$1.4M
Mechanisms of Synapse Vulnerability in Neurodegenerative DisordersR56NS105681 · NINDS · UNIVERSITY OF TEXAS MED BR GALVESTON · PI WAIRKAR, YOGESH P · 2019 to 2019
$591k
NCI NIH HHS P01 CA092584NCI NIH HHS R35 CA220430NEI NIH HHS R01 EY026089NIA NIH HHS P30 AG066509NIA NIH HHS R01 AG033082NINDS NIH HHS R01 NS065874NINDS NIH HHS R01 NS090390NINDS NIH HHS R01 NS100529NINDS NIH HHS R01 NS122571NINDS NIH HHS R35 NS116872NINDS NIH HHS R56 NS105681
6 · The paper itself

Abstract

Huntingtin (HTT) function is enigmatic, as the native protein plays critical roles in neuronal health, while mutant HTT (mHTT), carrying an expanded polyglutamine stretch, triggers neurotoxicity and contributes to the pathogenesis of Huntington's disease (HD). We recently found that HTT is part of a nuclear transcription-coupled DNA repair (TCR) complex with DNA repair enzymes including polynucleotide-kinase-3'-phosphatase (PNKP). This complex resolves DNA lesions during transcription to maintain genome integrity, while in HD, mHTT impairs the activity of this complex, resulting in accumulation of DNA lesions. Using molecular, cellular biology and computational methods, we find that HTT has a role in assembling a functional DNA repair complex in mitochondria. Together with mitochondrial RNA polymerase and transcription factors, HTT resolves mitochondrial DNA lesions to preserve mitochondrial genome integrity and function. Pathogenic mHTT impairs this activity, resulting in persistent DNA lesions and reduced mitochondrial function in HD. Importantly, restoring activity of this complex in a

Indexed as

CAG triplet repeat expansionsDrosophila model of Huntington’s diseaseHuntingtinHuntington’s diseaseMicrosatellite Repeat InstabilityMitochondrial DNA damage and mitochondrial dysfunctionmitochondrial genome maintenanceOxidative Stress and mitochondrial DNA damagePoly-glutamine repeat expansionsTranscription-coupled mitochondrial DNA repair

Identifiers

PMID40777236
PMCPMC12330591

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.