Mitochondrial complex I deficiency stratifies idiopathic Parkinson’s disease

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 Compta, Laura Molina-Porcel, Guido Alves, Ole-Bjørn Tysnes, Christian Dölle, Gonzalo S. Nido and Charalampos Tzoulis ()
Additional contact information
Irene H. Flønes: Haukeland University Hospital
Lilah Toker: Haukeland University Hospital
Dagny Ann Sandnes: Haukeland University Hospital
Martina Castelli: Haukeland University Hospital
Sepideh Mostafavi: Haukeland University Hospital
Njål Lura: Haukeland University Hospital
Omnia Shadad: Haukeland University Hospital
Erika Fernandez-Vizarra: University of Cambridge
Cèlia Painous: Universitat de Barcelona
Alexandra Pérez-Soriano: Universitat de Barcelona
Yaroslau Compta: Universitat de Barcelona
Laura Molina-Porcel: Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS)
Guido Alves: Stavanger University Hospital
Ole-Bjørn Tysnes: Haukeland University Hospital
Christian Dölle: Haukeland University Hospital
Gonzalo S. Nido: Haukeland University Hospital
Charalampos Tzoulis: Haukeland University Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47867-4

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