IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-47867-4.html
   My bibliography  Save this article

Mitochondrial complex I deficiency stratifies idiopathic Parkinson’s disease

Author

Listed:
  • Irene H. Flønes

    (Haukeland University Hospital
    University of Bergen
    University of Bergen)

  • Lilah Toker

    (Haukeland University Hospital
    University of Bergen
    University of Bergen)

  • Dagny Ann Sandnes

    (Haukeland University Hospital
    University of Bergen)

  • Martina Castelli

    (Haukeland University Hospital)

  • Sepideh Mostafavi

    (Haukeland University Hospital
    University of Bergen)

  • Njål Lura

    (Haukeland University Hospital
    University of Bergen)

  • Omnia Shadad

    (Haukeland University Hospital
    University of Bergen)

  • Erika Fernandez-Vizarra

    (University of Cambridge
    Veneto Institute of Molecular Medicine)

  • Cèlia Painous

    (Universitat de Barcelona)

  • Alexandra Pérez-Soriano

    (Universitat de Barcelona
    Centre Mèdic Teknon Grup Hospitalari Quirón Salud)

  • Yaroslau Compta

    (Universitat de Barcelona)

  • Laura Molina-Porcel

    (Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS)
    Biobanc-Hospital Clínic-IDIBAPS)

  • Guido Alves

    (Stavanger University Hospital
    University of Stavanger)

  • Ole-Bjørn Tysnes

    (Haukeland University Hospital
    University of Bergen)

  • Christian Dölle

    (Haukeland University Hospital
    University of Bergen
    University of Bergen)

  • Gonzalo S. Nido

    (Haukeland University Hospital
    University of Bergen
    University of Bergen)

  • Charalampos Tzoulis

    (Haukeland University Hospital
    University of Bergen
    University of Bergen)

Abstract

Idiopathic Parkinson’s disease (iPD) is believed to have a heterogeneous pathophysiology, but molecular disease subtypes have not been identified. Here, we show that iPD can be stratified according to the severity of neuronal respiratory complex I (CI) deficiency, and identify two emerging disease subtypes with distinct molecular and clinical profiles. The CI deficient (CI-PD) subtype accounts for approximately a fourth of all cases, and is characterized by anatomically widespread neuronal CI deficiency, a distinct cell type-specific gene expression profile, increased load of neuronal mtDNA deletions, and a predilection for non-tremor dominant motor phenotypes. In contrast, the non-CI deficient (nCI-PD) subtype exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and has a predilection for a tremor dominant phenotype. These findings constitute a step towards resolving the biological heterogeneity of iPD with implications for both mechanistic understanding and treatment strategies.

Suggested Citation

  • Irene H. Flønes & Lilah Toker & Dagny Ann Sandnes & Martina Castelli & Sepideh Mostafavi & Njål Lura & Omnia Shadad & Erika Fernandez-Vizarra & Cèlia Painous & Alexandra Pérez-Soriano & Yaroslau Compt, 2024. "Mitochondrial complex I deficiency stratifies idiopathic Parkinson’s disease," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47867-4
    DOI: 10.1038/s41467-024-47867-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-47867-4
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-47867-4?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Tohru Kitada & Shuichi Asakawa & Nobutaka Hattori & Hiroto Matsumine & Yasuhiro Yamamura & Shinsei Minoshima & Masayuki Yokochi & Yoshikuni Mizuno & Nobuyoshi Shimizu, 1998. "Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism," Nature, Nature, vol. 392(6676), pages 605-608, April.
    2. David A. Stroud & Elliot E. Surgenor & Luke E. Formosa & Boris Reljic & Ann E. Frazier & Marris G. Dibley & Laura D. Osellame & Tegan Stait & Traude H. Beilharz & David R. Thorburn & Agus Salim & Mich, 2016. "Accessory subunits are integral for assembly and function of human mitochondrial complex I," Nature, Nature, vol. 538(7623), pages 123-126, October.
    3. Nick Patterson & Alkes L Price & David Reich, 2006. "Population Structure and Eigenanalysis," PLOS Genetics, Public Library of Science, vol. 2(12), pages 1-20, December.
    4. Kip D. Zimmerman & Mark A. Espeland & Carl D. Langefeld, 2021. "A practical solution to pseudoreplication bias in single-cell studies," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Gyaneshwer Chaubey & Anurag Kadian & Saroj Bala & Vadlamudi Raghavendra Rao, 2015. "Genetic Affinity of the Bhil, Kol and Gond Mentioned in Epic Ramayana," PLOS ONE, Public Library of Science, vol. 10(6), pages 1-11, June.
    2. Kip D. Zimmerman & Ciaran Evans & Carl D. Langefeld, 2022. "Reply to: A balanced measure shows superior performance of pseudobulk methods in single-cell RNA-sequencing analysis," Nature Communications, Nature, vol. 13(1), pages 1-2, December.
    3. Daniel Svensson & Matilda Rentoft & Anna M Dahlin & Emma Lundholm & Pall I Olason & Andreas Sjödin & Carin Nylander & Beatrice S Melin & Johan Trygg & Erik Johansson, 2020. "A whole-genome sequenced control population in northern Sweden reveals subregional genetic differences," PLOS ONE, Public Library of Science, vol. 15(9), pages 1-18, September.
    4. Estavoyer, Maxime & François, Olivier, 2022. "Theoretical analysis of principal components in an umbrella model of intraspecific evolution," Theoretical Population Biology, Elsevier, vol. 148(C), pages 11-21.
    5. Felsenstein, Joseph, 2015. "Covariation of gene frequencies in a stepping-stone lattice of populations," Theoretical Population Biology, Elsevier, vol. 100(C), pages 88-97.
    6. Yaron Granot & Omri Tal & Saharon Rosset & Karl Skorecki, 2016. "On the Apportionment of Population Structure," PLOS ONE, Public Library of Science, vol. 11(8), pages 1-24, August.
    7. Özkan İş & Xue Wang & Joseph S. Reddy & Yuhao Min & Elanur Yilmaz & Prabesh Bhattarai & Tulsi Patel & Jeremiah Bergman & Zachary Quicksall & Michael G. Heckman & Frederick Q. Tutor-New & Birsen Can De, 2024. "Gliovascular transcriptional perturbations in Alzheimer’s disease reveal molecular mechanisms of blood brain barrier dysfunction," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    8. Hyosik Jang & Ian M Ehrenreich, 2012. "Genome-Wide Characterization of Genetic Variation in the Unicellular, Green Alga Chlamydomonas reinhardtii," PLOS ONE, Public Library of Science, vol. 7(7), pages 1-9, July.
    9. Mathieu Gautier & Denis Laloë & Katayoun Moazami-Goudarzi, 2010. "Insights into the Genetic History of French Cattle from Dense SNP Data on 47 Worldwide Breeds," PLOS ONE, Public Library of Science, vol. 5(9), pages 1-11, September.
    10. Xiaofeng Cai & Xuepeng Sun & Chenxi Xu & Honghe Sun & Xiaoli Wang & Chenhui Ge & Zhonghua Zhang & Quanxi Wang & Zhangjun Fei & Chen Jiao & Quanhua Wang, 2021. "Genomic analyses provide insights into spinach domestication and the genetic basis of agronomic traits," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    11. Lee, Anthony J. & Hibbs, Courtney & Wright, Margaret J. & Martin, Nicholas G. & Keller, Matthew C. & Zietsch, Brendan P., 2017. "Assessing the accuracy of perceptions of intelligence based on heritable facial features," Intelligence, Elsevier, vol. 64(C), pages 1-8.
    12. Thompson Katherine L. & Linnen Catherine R. & Kubatko Laura, 2016. "Tree-based quantitative trait mapping in the presence of external covariates," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 15(6), pages 473-490, December.
    13. Matthieu Bouaziz & Caroline Paccard & Mickael Guedj & Christophe Ambroise, 2012. "SHIPS: Spectral Hierarchical Clustering for the Inference of Population Structure in Genetic Studies," PLOS ONE, Public Library of Science, vol. 7(10), pages 1-17, October.
    14. Jacobo Pardo-Seco & Alberto Gómez-Carballa & Jorge Amigo & Federico Martinón-Torres & Antonio Salas, 2014. "A Genome-Wide Study of Modern-Day Tuscans: Revisiting Herodotus's Theory on the Origin of the Etruscans," PLOS ONE, Public Library of Science, vol. 9(9), pages 1-11, September.
    15. Andrey V Khrunin & Denis V Khokhrin & Irina N Filippova & Tõnu Esko & Mari Nelis & Natalia A Bebyakova & Natalia L Bolotova & Janis Klovins & Liene Nikitina-Zake & Karola Rehnström & Samuli Ripatti & , 2013. "A Genome-Wide Analysis of Populations from European Russia Reveals a New Pole of Genetic Diversity in Northern Europe," PLOS ONE, Public Library of Science, vol. 8(3), pages 1-9, March.
    16. Ilja M Nolte & Chris Wallace & Stephen J Newhouse & Daryl Waggott & Jingyuan Fu & Nicole Soranzo & Rhian Gwilliam & Panos Deloukas & Irina Savelieva & Dongling Zheng & Chrysoula Dalageorgou & Martin F, 2009. "Common Genetic Variation Near the Phospholamban Gene Is Associated with Cardiac Repolarisation: Meta-Analysis of Three Genome-Wide Association Studies," PLOS ONE, Public Library of Science, vol. 4(7), pages 1-10, July.
    17. Hoicheong Siu & Li Jin & Momiao Xiong, 2012. "Manifold Learning for Human Population Structure Studies," PLOS ONE, Public Library of Science, vol. 7(1), pages 1-18, January.
    18. Elodie Persyn & Richard Redon & Lise Bellanger & Christian Dina, 2018. "The impact of a fine-scale population stratification on rare variant association test results," PLOS ONE, Public Library of Science, vol. 13(12), pages 1-17, December.
    19. Andre Krumel Portella & Afroditi Papantoni & Catherine Paquet & Spencer Moore & Keri Shiels Rosch & Stewart Mostofsky & Richard S Lee & Kimberly R Smith & Robert Levitan & Patricia Pelufo Silveira & S, 2020. "Predicted DRD4 prefrontal gene expression moderates snack intake and stress perception in response to the environment in adolescents," PLOS ONE, Public Library of Science, vol. 15(6), pages 1-20, June.
    20. Lindsay Fernández-Rhodes & Jennifer R Malinowski & Yujie Wang & Ran Tao & Nathan Pankratz & Janina M Jeff & Sachiko Yoneyama & Cara L Carty & V Wendy Setiawan & Loic Le Marchand & Christopher Haiman &, 2018. "The genetic underpinnings of variation in ages at menarche and natural menopause among women from the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) Study: A trans-ethnic ," PLOS ONE, Public Library of Science, vol. 13(7), pages 1-21, July.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47867-4. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.