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Methods: To test whether CIH increases PD susceptibility, researchers established subtoxic PD models under CIH and analyzed lipid metabolism, focusing on lipid droplets (LDs), LD–mitochondrial interactions in dopaminergic neurons, and PPARα pathway modulation. Results: CIH worsened nigrostriatal dopamine neurodegeneration and motor impairment through PPARα-dependent disruption of Mfn2–Plin5 tethering, impairing LD turnover and promoting pathological LD accumulation. Conclusions: The LD–mitochondrial regulatory axis represents a therapeutic target for CIH-accelerated neurodegeneration.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/chronic-intermittent-hypoxia-increases-parkinsons-disease-susceptibility-via-ppar-mediated-lipid-droplet-mitochondrial-dysfunction/407288/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/chronic-intermittent-hypoxia-increases-parkinsons-disease-susceptibility-via-ppar-mediated-lipid-droplet-mitochondrial-dysfunction/407288.png","ImageObject",300,407,{"name":92,"@type":93},"Liam","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-03","2026-09-28",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",13,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What is the main question this study investigates about chronic intermittent hypoxia and Parkinson’s disease?","Question",{"text":113,"@type":114},"Whether chronic intermittent hypoxia (CIH) increases Parkinson’s disease (PD) susceptibility and through which underlying mechanisms it does so.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How were the effects of CIH tested in relation to PD susceptibility?",{"text":118,"@type":114},"Researchers used subtoxic PD mouse models exposed to CIH and analyzed lipid metabolism, lipid droplets, and LD–mitochondrial interactions in dopaminergic neurons, including PPARα pathway modulation.",{"name":120,"@type":111,"acceptedAnswer":121},"What mechanism did the study identify as central to CIH-driven PD pathology?",{"text":122,"@type":114},"A PPARα-dependent disruption of Mfn2–Plin5 tethering that impairs LD–mitochondrial interactions, compromises LD turnover, and promotes pathological LD accumulation in dopaminergic neurons.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},407288,1790811460,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146,"preview_page_count":4},8796095461564,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Theranostics 2026, Vol. 16, Issue 5 2466  \nIvyspring  \nInternational Publisher  \nTheranostics  \n2026; 16(5): 2466-2487. doi: 10.7150/thno.122944  \nResearch Paper  \nChronic intermittent hypoxia increases Parkinson's disease susceptibility via PPARα-mediated lipid droplet-mitochondrial dysfunction  \nMing-Rui Zhai*, Jie Pan*, Zhen-Huan Wu, Yu-Ying He, Kai-Run Zhang, Long Ren, Yu-Rong Wang, Yi-Bing Li, Jun Gao􀀍, Lei Xiao􀀍, Yue-Hua Liu\\#􀀍  \nDepartment of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, and the Institutes of Brain Science, Fudan University, China.  \n*These authors contributed equally.  \n\\#Lead contact.  \n􀀍 Corresponding authors: Jun Gao ([gaojun_kq@fudan.edu.cn](gaojun_kq@fudan.edu.cn)); Lei Xiao ([leixiao@fudan.edu.cn](leixiao@fudan.edu.cn)); Yue-Hua Liu ([liuyuehua@fudan.edu.cn](liuyuehua@fudan.edu.cn)) .  \n© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [https://ivyspring.com/terms](https://ivyspring.com/terms) for full terms and conditions.  \nReceived: 2025.08.02; Accepted: 2025.11.18; Published: 2026.01.01  \nAbstract  \nRationale: 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. Methods: 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 theneuroprotective potential of restoring LD–mitochondrial coupling in PD models.  \nResults: 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.  \nConclusions: 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.  \nKeywords: obstructive sleep apnea; chronic intermittent hypoxia; Parkinson’s disease; lipid droplet; mitochondria; PPARα  \nIntroduction  \nObstructive sleep apnea (OSA) is a common breathing disorder associated with sleep, marked by repeated episodes of apnea or hypopnea during sleep [1] . Its prevalence has steadily increased, affecting approximately 5–15% of the global population, with a particularly high incidence in the elderly [2] . Chronic intermittent hypoxia (CIH), a hallmark feature of OSA, has been shown to exert widespread  \ndetrimental effects on systemic health with a notable impact on the central nervous system (CNS) [3] . Accumulating evidence suggests that CIH triggers a cascade of pathophysiological events, including oxidative ","cbCaievomVoVumQP","https://ap.wps.com/l/cbCaievomVoVumQP","pdf",14746086,22,"English","# Abstract\n## Rationale\n## Methods\n## Results\n## Conclusions\n# Introduction","[{\"question\":\"What is the main question this study investigates about chronic intermittent hypoxia and Parkinson’s disease?\",\"answer\":\"Whether chronic intermittent hypoxia (CIH) increases Parkinson’s disease (PD) susceptibility and through which underlying mechanisms it does so.\"},{\"question\":\"How were the effects of CIH tested in relation to PD susceptibility?\",\"answer\":\"Researchers used subtoxic PD mouse models exposed to CIH and analyzed lipid metabolism, lipid droplets, and LD–mitochondrial interactions in dopaminergic neurons, including PPARα pathway modulation.\"},{\"question\":\"What mechanism did the study identify as central to CIH-driven PD pathology?\",\"answer\":\"A PPARα-dependent disruption of Mfn2–Plin5 tethering that impairs LD–mitochondrial interactions, compromises LD turnover, and promotes pathological LD accumulation in dopaminergic neurons.\"}]","Chronic intermittent hypoxia increases Parkinson's disease susceptibility via PPARα-mediated lipid droplet-mitochondrial dysfunction | PDF",1790572709,55]