Parkinson’s disease-related Miro1 mutation induces mitochondrial dysfunction and loss of dopaminergic neuronsin vitroandin vivo

Abstract

AbstractThe complex and heterogeneous nature of Parkinson’s disease (PD) is still not fully understood, however, increasing evidence supports mitochondrial impairments as a major driver of neurodegeneration in PD. Recently, the regulator of mitochondrial homeostasis Miro1 has been linked genetically and pathophysiologically to PD. Using 2D and 3D patient-based induced pluripotent stem cells models, including an isogenic control, showed that the Miro1 p.R272Q mutation leads to mitochondrial impairments including increased oxidative stress, disrupted mitochondrial bioenergetics and altered metabolism. This was accompanied by increased α-synuclein levels in 2D dopaminergic neurons and by a significant reduction of dopaminergic neurons within midbrain organoids. Knock-in mice expressing mutant p.R285Q Miro1 (orthologue of the human p.R272Q mutation) confirmed the PD-specific dopaminergic neuronal loss in the substantia nigra, accumulation of striatal phosphorylated α-synuclein accompanied by behavioral alterations. These findings demonstrate that mutant Miro1 is sufficient to comprehensively model PD-relevant phenotypesin vitroandin vivo, reinforcing its pivotal role in PD pathogenesis.