Chronic intermittent hypoxia increases Parkinson's disease susceptibility via PPARα-mediated lipid droplet-mitochondrial dysfunction

<b>Rationale:</b> Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), has emerged as a risk factor for Parkinson's Disease (PD). Yet, whether CIH increases PD susceptibility and the underlying mechanisms remain elusive. <b>Methods:</b> To investigate the impact of CIH on PD susceptibility, we established a series of subtoxic PD models subjected to CIH conditions. We analyzed lipid metabolism, with a particular focus on lipid droplets (LDs), in the pathogenesis of CIH-induced PD. Furthermore, we examined the significance of LD-mitochondrial interactions in mediating aberrant LD accumulation within dopaminergic (DA) neurons and identified the tethering proteins implicated in this process. Additionally, we utilized both systemic and region-specific modulation of the peroxisome proliferator-activated receptor α (PPARα) pathway to assess the neuroprotective potential of restoring LD-mitochondrial coupling in PD models. <b>Results:</b> We revealed that CIH significantly exacerbated nigrostriatal DA neurodegeneration and motor dysfunction in subtoxic PD models. Mechanistically, we identified a PPARα-dependent disruption of Mfn2-Plin5 tethering, which impaired LD-mitochondrial interactions, thereby compromising LD turnover and promoting pathological LD accumulation within DA neurons. Crucially, pharmacological interventions targeting the LD-mitochondrial axis, including strategies to enhance LD catabolism, inhibit mitochondrial fission, or restore LD-mitochondrial tethering, effectively mitigated nigrostriatal DA neurodegeneration in CIH-preconditioned subtoxic PD models. <b>Conclusions:</b> This study reveals a previously unrecognized LD-mitochondrial regulatory axis underlying CIH-associated PD pathology and highlights its potential as a therapeutic target against CIH-accelerated neurodegeneration.