Hypoxia ameliorates neurodegeneration and movement disorder in a mouse model of Parkinson’s disease
Eizo Marutani, María Miranda, Timothy Durham, Sharon H. Kim, Drèson L. Russell, Presli P. Wiesenthal, Paul Lichtenegger, Marissa Menard, Charlotte F. Brzozowski, Haobo Li, Gary Ruvkun, Joshua D. Meisel, Laura A. Volpicelli‐Daley, Vamsi K. Mootha, Fumito Ichinose
Abstract
Parkinson's disease (PD) is characterized by inclusions of α-synuclein (α-syn) and mitochondrial dysfunction in dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc). Patients with PD anecdotally experience symptom improvement at high altitude; chronic hypoxia prevents the development of Leigh-like brain disease in mice with mitochondrial complex I deficiency. Here we report that intrastriatal injection of α-syn preformed fibrils (PFFs) in mice resulted in neurodegeneration and movement disorder, which were prevented by continuous exposure to 11% oxygen. Specifically, PFF-induced α-syn aggregation resulted in brain tissue hyperoxia, lipid peroxidation and DA neurodegeneration in the SNpc of mice breathing 21% oxygen, but not in those breathing 11% oxygen. This neuroprotective effect of hypoxia was also observed in Caenorhabditis elegans. Moreover, initiating hypoxia 6 weeks after PFF injection reversed motor dysfunction and halted further DA neurodegeneration. These results suggest that hypoxia may have neuroprotective effects downstream of α-syn aggregation in PD, even after symptom onset and neuropathological changes.