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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
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    References listed on IDEAS

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