{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T13:10:20Z","timestamp":1793106620473,"version":"4.5.0"},"reference-count":73,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Parkinson\u2019s disease (PD) is traditionally defined by dopaminergic degeneration and\n                      <jats:italic>\u03b1<\/jats:italic>\n                      -synuclein aggregation. However, mounting evidence supports a multifactorial and systemic pathophysiology that extends beyond the central nervous system. This narrative review explores the interconnected mechanisms underlying sporadic PD, including environmental exposures, gut dysbiosis,\n                      <jats:italic>\u03b1<\/jats:italic>\n                      -synuclein pathology and propagation, systemic and neuroinflammation, metabolic dysfunctions (notably insulin and lipid metabolism), sleep disturbances, glymphatic impairment, and proteostatic failure.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The review highlights how\n                      <jats:italic>\u03b1<\/jats:italic>\n                      -synuclein pathology can originate peripherally, particularly in the enteric nervous system, and propagate to the brain via neuronal or hematogenous routes. It also examines the synergistic roles of systemic inflammation, immune dysregulation, mitochondrial dysfunction, and impaired protein clearance in promoting neurodegeneration.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Collectively, these findings support a reconceptualization of PD as a systemic neurodegenerative disorder involving complex crosstalk between peripheral and central pathways. Understanding these multifaceted interactions opens new avenues for early diagnosis, biomarker discovery, and disease-modifying therapeutic strategies targeting the gut-brain axis, metabolic homeostasis, and proteostasis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2025.1664269","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T06:34:13Z","timestamp":1765521253000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Parkinson\u2019s disease physiopathology\u2014beyond the \u03b1-synuclein aggregation: a narrative review"],"prefix":"10.3389","volume":"17","author":[{"given":"Victor Fellipe Bispo","family":"Macedo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa Karine Bispo","family":"Macedo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge Artur Pe\u00e7anha","family":"de Miranda Coelho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alana Madeiro","family":"de Melo Barboza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"107177","DOI":"10.1016\/j.parkreldis.2024.107177","article-title":"Neuroinflammation in Parkinson\u2019s disease: a study with [11C]PBR28 PET and cerebrospinal fluid markers","volume":"130","author":"Al-Abdulrasul","year":"2024","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"10251","DOI":"10.1038\/ncomms10251","article-title":"Intracellular repair of oxidation-damaged \u03b1-synuclein fails to target C-terminal modification sites","volume":"7","author":"Andr\u00e9s","year":"2016","journal-title":"Nat. Commun."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1002\/mdc3.14254","article-title":"Intersection of sleep disorders and Parkinson disease: unveiling the bidirectional relationship","volume":"12","author":"Antelmi","year":"2024","journal-title":"Mov. Disord. Clin. Pract."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"112444","DOI":"10.1016\/j.exger.2024.112444","article-title":"Association between increased and decreased gut microbiota abundance and Parkinson\u2019s disease: a systematic review and subgroup meta-analysis","volume":"191","author":"Bai","year":"2024","journal-title":"Exp. Gerontol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"218","DOI":"10.3389\/fneur.2019.00218","article-title":"Parkinson\u2019s disease and the environment","volume":"10","author":"Ball","year":"2019","journal-title":"Front. Neurol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"718356","DOI":"10.3389\/fnut.2021.718356","article-title":"Inflammatory and microbiota-related regulation of the intestinal epithelial barrier","volume":"8","author":"Barbara","year":"2021","journal-title":"Front. Nutr."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1146\/annurev-biochem-062917-011931","article-title":"Structure and function of the 26S proteasome","volume":"87","author":"Bard","year":"2018","journal-title":"Annu. Rev. Biochem."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1002\/mds.29257","article-title":"Blood markers of inflammation, neurodegeneration, and cardiovascular risk in early Parkinson\u2019s disease","volume":"1","author":"Bartl","year":"2022","journal-title":"Mov. Disord."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1038\/s41419-021-03441-0","article-title":"Expanding the role of proteasome homeostasis in Parkinson\u2019s disease: beyond protein breakdown","volume":"12","author":"Bi","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"21579","DOI":"10.1021\/acs.est.5c03787","article-title":"Are clouds a neglected reservoir of pesticides?","volume":"59","author":"Bianco","year":"2025","journal-title":"Environ. Sci. Technol."},{"key":"ref11","doi-asserted-by":"publisher","DOI":"10.1101\/2022.12.23.22283910","article-title":"Striatal dopaminergic asymmetry as a marker of brain-first and body-first subtypes in de novo Parkinson\u2019s disease","author":"Boertien","year":"2022","journal-title":"medRxiv"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1038\/nrd.2018.109","article-title":"Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing","volume":"17","author":"Boland","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1007\/s00441-004-0956-9","article-title":"Stages in the development of Parkinson\u2019s disease-related pathology","volume":"318","author":"Braak","year":"2004","journal-title":"Cell Tissue Res."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1002\/mds.30067","article-title":"Environmental risk factors for Parkinson\u2019s disease: a critical review and policy implications","volume":"40","author":"Brolin","year":"2024","journal-title":"Mov. Disord."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.1002\/mds.29432","article-title":"The endotoxin hypothesis of Parkinson\u2019s disease","volume":"38","author":"Brown","year":"2023","journal-title":"Mov. 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Bull."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1292","DOI":"10.1126\/science.1101738","article-title":"Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy","volume":"305","author":"Cuervo","year":"2004","journal-title":"Science"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"4163","DOI":"10.1038\/s41467-022-31591-y","article-title":"Orexin neurons inhibit sleep to promote arousal","volume":"13","author":"De Luca","year":"2022","journal-title":"Nat. Commun."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"105312","DOI":"10.1016\/j.nbd.2021.105312","article-title":"The industrial solvent trichloroethylene induces LRRK2 kinase activity and dopaminergic neurodegeneration in a rat model of Parkinson\u2019s disease","volume":"153","author":"De Miranda","year":"2021","journal-title":"Neurobiol. Dis."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1002\/mds.25462","article-title":"Lysosomal impairment in Parkinson\u2019s disease","volume":"28","author":"Dehay","year":"2013","journal-title":"Mov. Disord."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1136\/oem.2006.027003","article-title":"Environmental risk factors for Parkinson\u2019s disease and parkinsonism: the Geoparkinson study","volume":"64","author":"Dick","year":"2007","journal-title":"Occup. Environ. Med."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"107321","DOI":"10.1016\/j.parkreldis.2025.107321","article-title":"Aggregated \u03b1-synuclein in erythrocytes as a potential biomarker for idiopathic Parkinson\u2019s disease","volume":"133","author":"Dimoula","year":"2025","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/j.taap.2005.06.003","article-title":"Pyrethroid pesticide-induced alterations in dopamine transporter function","volume":"211","author":"Elwan","year":"2006","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref27","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-025-02925-z","article-title":"Sphingolipidoses: expanding the spectrum of \u03b1-synucleinopathies","author":"Erskine","year":"2025","journal-title":"J. Neural Transm."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"a033993","DOI":"10.1101\/cshperspect.a033993","article-title":"The autophagy lysosomal pathway and neurodegeneration","volume":"12","author":"Finkbeiner","year":"2019","journal-title":"Cold Spring Harb. Perspect. 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Pract."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1677","DOI":"10.3233\/JPD-212761","article-title":"Asymmetric dopaminergic dysfunction in brain-first versus body-first Parkinson\u2019s disease subtypes","volume":"11","author":"Knudsen","year":"2021","journal-title":"J. Parkinsons Dis."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"e2433602","DOI":"10.1001\/jamanetworkopen.2024.33602","article-title":"Air pollution and Parkinson disease in a population-based study","volume":"7","author":"Krzyzanowski","year":"2024","journal-title":"JAMA Netw. Open"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"12924","DOI":"10.1074\/jbc.M306390200","article-title":"Proteasomal inhibition by alpha-synuclein filaments and oligomers","volume":"279","author":"Lindersson","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1111\/j.1471-4159.2009.06497.x","article-title":"Trichloroethylene induces dopaminergic neurodegeneration in fisher 344 rats","volume":"112","author":"Liu","year":"2010","journal-title":"J. Neurochem."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"264","DOI":"10.3389\/fncel.2020.00264","article-title":"Homeostatic roles of the Proteostasis network in dendrites","volume":"14","author":"Lottes","year":"2020","journal-title":"Front. Cell. Neurosci."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"1625","DOI":"10.3390\/biomedicines9111625","article-title":"Macroautophagy and mitophagy in neurodegenerative disorders: focus on therapeutic interventions","volume":"9","author":"Magalh\u00e3es","year":"2021","journal-title":"Biomedicine"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/s0304-3940(00)01701-8","article-title":"Proteasomal function is impaired in substantia nigra in Parkinson\u2019s disease","volume":"297","author":"McNaught","year":"2001","journal-title":"Neurosci. Lett."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"1740","DOI":"10.1002\/mds.29959","article-title":"Metagenomic analysis reveals large-scale disruptions of the gut microbiome in Parkinson\u2019s disease","volume":"39","author":"Metcalfe-Roach","year":"2024","journal-title":"Mov. Disord."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1016\/j.molmed.2015.04.005","article-title":"Type 2 diabetes as a protein misfolding disease","volume":"21","author":"Mukherjee","year":"2015","journal-title":"Trends Mol. Med."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1002\/mds.29369","article-title":"Peripheral inflammation is associated with dopaminergic degeneration in Parkinson\u2019s disease","volume":"5","author":"Mu\u00f1oz-Delgado","year":"2023","journal-title":"Mov. Disord."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1038\/s41531-022-00397-6","article-title":"Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology","volume":"8","author":"Navarro-Romero","year":"2022","journal-title":"NPJ Parkinsons Dis."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"107081","DOI":"10.1016\/j.parkreldis.2024.107081","article-title":"Effects of antimicrobial exposure on the risk of Parkinson\u2019s disease","volume":"127","author":"Pal","year":"2024","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"4006","DOI":"10.1016\/j.neuron.2023.11.0202022","article-title":"Serine-129 phosphorylation of \u03b1-synuclein is a trigger for physiologic protein-protein interactions and synaptic function","volume":"24","author":"Parra-Rivas","year":"2022","journal-title":"Neuron"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"2803","DOI":"10.1038\/s41467-023-38215-z","article-title":"A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides","volume":"14","author":"Paul","year":"2023","journal-title":"Nat. Commun."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"5379","DOI":"10.1007\/s12035-022-02897-1","article-title":"Role of ubiquitin-proteasome and autophagy-lysosome pathways in \u03b1-synuclein aggregate clearance","volume":"59","author":"Sahoo","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"7674","DOI":"10.1038\/s41467-023-42862-7","article-title":"A reversible state of hypometabolism in a human cellular model of sporadic Parkinson\u2019s disease","volume":"14","author":"Schmidt","year":"2023","journal-title":"Nat. Commun."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1002\/mds.30124","article-title":"It takes guts: a novel model for gut-to-brain propagation of alpha-Synuclein and tau","volume":"40","author":"Scholz","year":"2025","journal-title":"Mov. Disord."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"2173","DOI":"10.1002\/mds.29209","article-title":"Uric acid in Parkinson\u2032s disease: what is the connection?","volume":"37","author":"Seifar","year":"2022","journal-title":"Mov. Disord."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"2155","DOI":"10.1002\/mds.30023","article-title":"Cholinergic basal forebrain integrity and cognition in Parkinson\u2019s disease: a reappraisal of magnetic resonance imaging evidence","volume":"39","author":"Slater","year":"2024","journal-title":"Mov. Disord."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"107615","DOI":"10.1016\/j.phrs.2025.107615","article-title":"High-fat diet and neuroinflammation: the role of mitochondria","volume":"212","author":"Song","year":"2025","journal-title":"Pharmacol. Res."},{"key":"ref58","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1002\/mds.29331","article-title":"Neuron-derived misfolded \u03b1-synuclein in blood: a potential biomarker for Parkinson\u2019s disease?","volume":"38","author":"Streubel-Gallasch","year":"2023","journal-title":"Mov. 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Disord."},{"key":"ref62","doi-asserted-by":"publisher","first-page":"107132","DOI":"10.1016\/j.parkreldis.2024.107132","article-title":"Anti-diabetic drug use and reduced risk of Parkinson\u2019s disease: a community-based cohort study","volume":"128","author":"Violetta","year":"2024","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref63","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1002\/mds.30144","article-title":"Effects of Montelukast on Neuroinflammation in Parkinson\u2019s Disease: An Open Label Safety and Tolerability Trial with CSF Markers and [11C]PBR28 PET","volume":"4","author":"Wallin","year":"2024","journal-title":"Mov. Disord."},{"key":"ref64","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1083\/jcb.201003122","article-title":"\u03b1-synuclein impairs macroautophagy: implications for Parkinson\u2019s disease","volume":"190","author":"Winslow","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref65","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.cellsig.2018.01.006","article-title":"Dopamine transporter trafficking is regulated by neutral sphingomyelinase 2\/ceramide kinase","volume":"44","author":"Won","year":"2018","journal-title":"Cell. Signal."},{"key":"ref66","doi-asserted-by":"publisher","first-page":"2166","DOI":"10.4161\/auto.26451","article-title":"LAMP2A as a therapeutic target in Parkinson disease","volume":"9","author":"Xilouri","year":"2013","journal-title":"Autophagy"},{"key":"ref67","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1007\/s12035-014-9057-2","article-title":"Fenpropathrin, a widely used pesticide, causes dopaminergic degeneration","volume":"53","author":"Xiong","year":"2015","journal-title":"Mol. 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