RESTORATION OF NADH OXIDATION IN DOPAMINERGIC NEURONS PREVENTS PARKINSONISM

Parkinson’s disease (PD) is a progressive neurodegenerative disorder whose etiology remains poorly understood, although mitochondrial dysfunction is now recognized to play a major role in the pathophysiology of PD. Indeed, a genetically modified mouse lacking mitochondrial complex I (MCI) in dopamine neurons (MCI-Park model) develops a progressive and severe nigrostriatal degeneration associated with locomotor decline, as well as pronounced alterations in sleep architecture, including insomnia and sleep fragmentation. These findings suggest that dopaminergic degeneration contribute not only to motor impairment but also to non-motor symptoms such as sleep disturbances.
To identify therapeutic strategies capable of restoring mitochondrial activity, we generated the MCI-Park/NDI1 model, expressing the yeast NADH-quinone oxidoreductase (NDI1), an alternative NADH dehydrogenase, selectively in dopaminergic neurons with MCI dysfunction. To determine whether the parkinsonian phenotype could be rescued in MCI-Park/NDI1 mice, we compared them to their pathological MCI-Park and wild-type littermates.
Phenotypic analyses indicate that MCI-Park/NDI1 mice exhibit a full behavioral rescue, recovering fine motor skills and locomotor coordination to wild-type levels. At the molecular level, they show normal numbers of tyrosine hydroxylase–positive dopaminergic neurons and restored dopamine content in the striatum and substantia nigra pars compacta (SNc), as measured by HPLC. Remarkably, NDI1 expression restores total sleep amount, including both Rapid Eye Movement (REM) sleep and non-REM sleep. These findings demonstrate that restoring mitochondrial function in dopaminergic neurons can ameliorate key aspects of PD-related sleep pathology. Mitochondria-targeted interventions may therefore represent a viable strategy to treat non-motor symptoms of PD and improve patient quality of life.