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Functional iron deficiency at the core of Parkinson’s disease pathobiology - Viewpoint","","The Viewpoint “Isn’t it ironic? Functional iron deficiency at the core of Parkinson’s disease pathobiology” argues that Parkinson’s disease (PD) may involve impaired iron bioavailability rather than the dominant idea of neuronal iron overload. Clinical trials with the brain-penetrant iron chelator deferiprone (DFP) worsen PD symptoms, especially in drug-naive patients, challenging the iron overload model. The authors connect functional iron deficiency to reduced bioavailable Fe2+, disrupted mitochondrial respiration, and decreased dopamine synthesis, and discuss historical evidence and mechanistic rationale for restoring iron availability and using iron therapy.",{"@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/isnt-it-ironic-functional-iron-deficiency-at-the-core-of-parkinsons-disease-pathobiology-viewpoint/413790/",{"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/isnt-it-ironic-functional-iron-deficiency-at-the-core-of-parkinsons-disease-pathobiology-viewpoint/413790.png","ImageObject",300,407,{"name":92,"@type":93},"Himbo","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",14,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"Why do the authors question the iron overload hypothesis in Parkinson’s disease?","Question",{"text":113,"@type":114},"Because clinical trials using the brain-penetrant iron chelator deferiprone (DFP) have shown symptom worsening in PD, particularly in drug-naive patients, which contradicts the expectation that reducing excess neuronal iron would help.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"What is functional iron deficiency as described in the text?",{"text":118,"@type":114},"A condition where total iron is normal or elevated, but bioavailable ferrous iron (Fe2+) is reduced due to sequestration, limiting iron-dependent cellular processes.",{"name":120,"@type":111,"acceptedAnswer":121},"How might restoring iron bioavailability affect PD symptoms?",{"text":122,"@type":114},"The text links improved iron bioavailability to stimulation of tyrosine hydroxylase (TH), an iron-dependent, rate-limiting enzyme in endogenous dopamine production, and suggests this could counter key PD hallmarks.","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},413790,1790764099,{"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":81,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":39,"preview_page_count":4},687197100911,"https://ap-avatar.wpscdn.com/avatar/a000239b6f1da00475?x-image-process=image/resize,m_fixed,w_180,h_180&k=1785132997149421697","The Journal of Clinical Investigation VIEWPOINT  \nIsn’t it ironic? Functional iron deficiency at the core of Parkinson’s disease pathobiology  \nIan Peikon1 and Nancy C. Andrews2  \n1Cajal Therapeutics Inc., Seattle, Washington, USA. 2Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.  \nAberrant iron homeostasis has been implicated in Parkinson’s disease (PD) for decades. Currently, the dominant view is that iron overload in neurons of the substantia nigra drives pathogenic neurodegeneration. This view is supported by histology, MRI studies, and the discovery of ferroptosis, an iron-dependent form of cell death. However, recent clinical trials using the brain-penetrant iron chelator deferiprone (DFP) have shown that iron removal worsens PD symptoms, particularly in drug-naive patients (1, 2), challenging this model.  \nAn alternative explanation for iron’s role in PD is functional iron deficiency, a state in which the total amount of iron is normal or elevated, but bioavailable ferrous iron (Fe²+) is reduced due to sequestration. Functional iron deficiency is well documented in inflammatory conditions (3), and the effects of iron deficiency on iron-dependent processes, including impaired mitochondrial respiration and decreased dopamine synthesis, align closely with PD hallmarks (4) . Historical reports suggest that modest iron supplementation can improve PD symptoms (5), likely via stimulation of tyrosine hydroxylase (TH), the iron-dependent and rate-limiting enzyme in endogenous dopamine production. A similar rationale underlies the use of i.v. iron therapy in restless leg syndrome (RLS), another dopaminergic disorder (6) .  \nTaken together, these observations point toward potential clinical benefit from restoring iron bioavailability and harm from limiting it in PD. Here, we detail the data suggesting that functional iron defi-  \nciency could be a key mechanism in PD and argue that pursuing this concept could lead to novel therapeutic avenues.  \nFrom l-DOPA to iron therapy The first breakthrough in PD treatment came in the early 1960s when Birkmayer and Hornykiewicz showed that l-3,4-dioxyphenylalanine (l-DOPA) alleviated motor symptoms caused by dopamine deficiency in the basal ganglia, a group of midbrain nuclei that includes the substantia nigra (5) . This approach was later justified by the finding that TH activity, which converts tyrosine to l-DOPA, was diminished in the PD brain (6) . It was later shown that TH isan iron-dependent enzyme (7) and that iron could dramatically stimulate TH activity inhuman brain homogenates (8), prompting Birkmayer to explore iron therapy as a treatment for PD. In the 1980s, Birkmayer reported striking improvements in a study of 100 PD patients given iron supplementation, with some able to stop dopaminergic drugs entirely (9) . While this study was not conducted in a controlled clinical trial setting, it nevertheless suggests the potential of iron therapy in PD. It is surprising that no additional work has been done in this vein, especially given that RLS, which is also a dopaminergic disorder, is treated with iron therapy as standard of care (10) .  \nThe rise of the iron overload hypothesis  \nDespite indications that iron therapy could be beneficial in PD, the field shifted toward the now dominant hypothesis of iron over-  \nConflict of interest: NCA serves on the Boards of Directors for Novartis, Charles River Laboratories, and Maze Therapeutics and receives both cash and equity compensation. She also serves on the Scientific Advisory Board for Dyne Therapeutics and receives cash compensation in addition to an earlier equity grant. She has been a consultant to Cajal Therapeuticsand has been invited to join their Scientific Advisory Board. She is an elected member and serves as Home Secretary of the National Academy of Sciences, which reimburses Boston Children’s Hospital for 25% of her salary. She holds a patent entitled “Method for ","cbCaiqIXQsdLkuxq","https://ap.wps.com/l/cbCaiqIXQsdLkuxq","pdf",314120,"English","# Isn’t it ironic? Functional iron deficiency at the core of Parkinson’s disease pathobiology\n## From l-DOPA to iron therapy\n## The rise of the iron overload hypothesis\n## Iron overload may be an illusion","[{\"question\":\"Why do the authors question the iron overload hypothesis in Parkinson’s disease?\",\"answer\":\"Because clinical trials using the brain-penetrant iron chelator deferiprone (DFP) have shown symptom worsening in PD, particularly in drug-naive patients, which contradicts the expectation that reducing excess neuronal iron would help.\"},{\"question\":\"What is functional iron deficiency as described in the text?\",\"answer\":\"A condition where total iron is normal or elevated, but bioavailable ferrous iron (Fe2+) is reduced due to sequestration, limiting iron-dependent cellular processes.\"},{\"question\":\"How might restoring iron bioavailability affect PD symptoms?\",\"answer\":\"The text links improved iron bioavailability to stimulation of tyrosine hydroxylase (TH), an iron-dependent, rate-limiting enzyme in endogenous dopamine production, and suggests this could counter key PD hallmarks.\"}]","Isn’t it ironic? Functional iron deficiency at the core of Parkinson’s disease pathobiology - Viewpoint | PDF",1790595775]