Mitochondrial complex I deficiency stratifies idiopathic Parkinson’s disease
Flønes, Irene; Toker, Lilah; Sandnes, Dagny Ann; Castelli, Martina Galatea; Mostafavi, Sepideh; Lura, Njål; Shadad, Omnia; Fernandez-Vizarra, Erika; Painous, Cèlia; Pérez-Soriano, Alexandra; Compta, Yaroslau; Molina-Porcel, Laura; Alves, Guido Werner; Tysnes, Ole-Bjørn; Dölle, Christian; Sanchez Nido, Gonzalo; Tzoulis, Charalampos
Journal article, Peer reviewed
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Date
2024Metadata
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- Department of Clinical Medicine [2206]
- Registrations from Cristin [11332]
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.