{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T13:50:47Z","timestamp":1784296247870,"version":"3.55.0"},"reference-count":169,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"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:p>The presence of <jats:italic>\u03b1<\/jats:italic>-synuclein pathology in peripheral nervous system neurons is linked to early prodromal, non-motor symptoms in a segment of Parkinson\u2019s disease (PD) patients referred to as \u201cbody-first.\u201d These features of the disease suggest a convergence of environmental, genetic, immune and age-related factors within the enteric nervous system as initiating triggers of disease. This review explores the changes in the gut microbiome and intestinal permeability that may drive systemic inflammation and precede neurodegeneration in PD. The pathways leading to the formation of <jats:italic>\u03b1<\/jats:italic>-synuclein aggregates are explored as well as their role in transneuronal propagation and the spreading of pathology within the brain. Lastly, advances in systemic gene therapy that could be used to target multiple PD-affected organs following systemic injection are highlighted. By integrating insights from molecular biology and clinical research, it may be possible to shed light on the multifactorial etiology of PD and the interconnectedness of the gut and brain, which could lead to novel diagnostic and therapeutic strategies.<\/jats:p>","DOI":"10.3389\/fnagi.2025.1600782","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T05:28:26Z","timestamp":1759987706000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Parkinson\u2019s disease beyond the brain: implications for treatments"],"prefix":"10.3389","volume":"17","author":[{"given":"Setareh","family":"Malekian Naeini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc Danzell","family":"Lopez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul E.","family":"Fraser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anurag","family":"Tandon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"ref1","first-page":"2120","article-title":"Tunneling nanotubes spread fibrillar \u03b1-synuclein by intercellular trafficking of lysosomes","author":"Abounit","year":"2016"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1186\/s13024-021-00427-6","article-title":"Relationships of gut microbiota, short-chain fatty acids, inflammation, and the gut barrier in Parkinson\u2019s disease","volume":"16","author":"Aho","year":"2021","journal-title":"Mol. Neurodegener."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"593026","DOI":"10.3389\/fphys.2020.593026","article-title":"Blood\u2013brain barrier leakage is increased in Parkinson\u2019s disease","volume":"11","author":"Al-Bachari","year":"2020","journal-title":"Front. Physiol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1038\/s41531-021-00215-5","article-title":"Parkinson's disease patients' short chain fatty acids production capacity after in vitro fecal fiber fermentation","volume":"7","author":"Baert","year":"2021","journal-title":"NPJ Parkinsons Dis."},{"key":"ref5","first-page":"396","article-title":"Unraveling gut microbiota in Parkinson's disease and atypical parkinsonism","author":"Barichella","year":"2019"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1833","DOI":"10.3233\/JPD-212733","article-title":"Vagus nerve and stomach Synucleinopathy in Parkinson's disease, incidental Lewy body disease, and Normal elderly subjects: evidence against the 'body-first' hypothesis","volume":"11","author":"Beach","year":"2021","journal-title":"J. Parkinsons Dis."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"2229","DOI":"10.1021\/acschemneuro.8b00733","article-title":"Lipopolysaccharide from gut microbiota modulates \u03b1-synuclein aggregation and alters its biological function","volume":"10","author":"Bhattacharyya","year":"2019","journal-title":"ACS Chem. Neurosci."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.pneurobio.2005.06.004","article-title":"Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism","volume":"76","author":"Block","year":"2005","journal-title":"Prog. Neurobiol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"455","DOI":"10.3233\/JPD-202481","article-title":"The \u03b1-Synuclein origin and connectome model (SOC model) of Parkinson's disease: explaining motor asymmetry, non-motor phenotypes, and cognitive decline","volume":"11","author":"Borghammer","year":"2021","journal-title":"J. Parkinsons Dis."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"S281","DOI":"10.3233\/JPD-191721","article-title":"Brain-first versus gut-first Parkinson\u2019s disease: a hypothesis","volume":"9","author":"Borghammer","year":"2019","journal-title":"J. Parkinson\u2019s Dis."},{"key":"ref11","first-page":"67","article-title":"Gastric alpha-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology","author":"Braak","year":"2006"},{"key":"ref12","first-page":"197","article-title":"Staging of brain pathology related to sporadic Parkinson\u2019s disease","author":"Braak","year":"2003"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1007\/s00702-002-0808-2","article-title":"Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen","volume":"110","author":"Braak","year":"2003","journal-title":"J. Neural Transm."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1172\/JCI36470","article-title":"Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease","volume":"119","author":"Brochard","year":"2009","journal-title":"J. Clin. Inv."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"15014","DOI":"10.1038\/npjparkd.2015.14","article-title":"Why is there motor deterioration in Parkinson\u2019s disease during systemic infections-a hypothetical view","volume":"1","author":"Brugger","year":"2015","journal-title":"NPJ Parkinsons Dis."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41419-023-05672-9","article-title":"Alpha-synuclein in Parkinson\u2019s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction","volume":"14","author":"Calabresi","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1332","DOI":"10.1007\/s00415-012-6801-2","article-title":"Gastrointestinal manifestations in Parkinson\u2019s disease: prevalence and occurrence before motor symptoms","volume":"260","author":"Cersosimo","year":"2013","journal-title":"J. Neurol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/s41593-020-0589-7","article-title":"Gut-seeded \u03b1-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice","volume":"23","author":"Challis","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1038\/nn.4593","article-title":"Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems","volume":"20","author":"Chan","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"218","DOI":"10.3389\/fnmol.2019.00218","article-title":"Gut inflammation in association with pathogenesis of Parkinson\u2019s disease","volume":"12","author":"Chen","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1002\/ana.20682","article-title":"Nonsteroidal antiinflammatory drug use and the risk for Parkinson's disease","volume":"58","author":"Chen","year":"2005","journal-title":"Ann. Neurol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.ebiom.2018.03.030","article-title":"Sodium butyrate inhibits inflammation and maintains epithelium barrier integrity in a TNBS-induced inflammatory bowel disease mice model","volume":"30","author":"Chen","year":"2018","journal-title":"EBioMedicine"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"2242","DOI":"10.1016\/j.neuron.2022.05.003","article-title":"Engineered AAVs for non-invasive gene delivery to rodent and non-human primate nervous systems","volume":"110","author":"Chen","year":"2022","journal-title":"Neuron"},{"key":"ref24","first-page":"1059","article-title":"Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease","author":"Chen","year":"2003"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/srep34477","article-title":"Exposure to the functional bacterial amyloid protein curli enhances alpha-synuclein aggregation in aged Fischer 344 rats and Caenorhabditis elegans","volume":"6","author":"Chen","year":"2016","journal-title":"Sci. Rep."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"7438","DOI":"10.1074\/jbc.M112.439497","article-title":"\u03b1-synuclein membrane association is regulated by the Rab3a recycling machinery and presynaptic activity","volume":"288","author":"Chen","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"38582","DOI":"10.1038\/s41467-023-38582-7","article-title":"Functional gene delivery to and across brain vasculature of systemic AAVs with endothelial-specific tropism in rodents and broad tropism in primates","volume":"14","author":"Chen","year":"2023","journal-title":"Nat. Commun."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.jmb.2005.07.028","article-title":"The formation of Escherichia coli curli amyloid fibrils is mediated by prion-like peptide repeats","volume":"352","author":"Cherny","year":"2005","journal-title":"J. Mol. Biol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1038\/s41598-018-19646-x","article-title":"Oral administration of Proteus mirabilis damages dopaminergic neurons and motor functions in mice","volume":"8","author":"Choi","year":"2018","journal-title":"Sci. Rep."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"6593","DOI":"10.1111\/febs.15674","article-title":"Molecular events underlying the cell-to-cell transmission of \u03b1-synuclein","volume":"288","author":"Choi","year":"2021","journal-title":"FASEB J"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1002\/mds.26473","article-title":"Alpha-synuclein in gastric and colonic mucosa in Parkinson's disease: limited role as a biomarker","volume":"31","author":"Chung","year":"2016","journal-title":"Mov. Disord."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"318","DOI":"10.4274\/balkanmedj.galenos.2022.2022-7-100","article-title":"Neuroinflammation in Parkinson\u2019s disease and its treatment opportunities","volume":"39","author":"\u00c7\u0131nar","year":"2022","journal-title":"Balkan Med. J."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1002\/mds.28052","article-title":"Microbiota composition and metabolism are associated with gut function in Parkinson's disease","volume":"35","author":"Cirstea","year":"2020","journal-title":"Mov. Disord."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1126\/science.1129462","article-title":"\u03b1-Synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models","volume":"313","author":"Cooper","year":"2006","journal-title":"Science"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1877","DOI":"10.1152\/physrev.00018.2018","article-title":"The microbiota-gut-brain Axis","volume":"99","author":"Cryan","year":"2019","journal-title":"Physiol. Rev."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/1750-1326-7-42","article-title":"Exosomal cell-to-cell transmission of alpha synuclein oligomers","volume":"7","author":"Danzer","year":"2012","journal-title":"Mol. Neurodegener."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1418","DOI":"10.1016\/S0022-3565(25)13090-5","article-title":"Effect of endotoxin on permeability of bovine cerebral endothelial cell layers in vitro","volume":"277","author":"de Vries","year":"1996","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref38","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/0165-5728(95)00148-4","article-title":"The influence of cytokines on the integrity of the blood-brain barrier in vitro","volume":"64","author":"De Vries","year":"1996","journal-title":"J. Neuroimmunol."},{"key":"ref39","first-page":"2413","article-title":"Lipopolysaccharide mouse models for Parkinson\u2019s disease research: a critical appraisal","author":"Deng","year":"2022"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/nbt.3440","article-title":"Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain","volume":"34","author":"Deverman","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.nbd.2012.09.007","article-title":"Colonic inflammation in Parkinson's disease","volume":"50","author":"Devos","year":"2013","journal-title":"Neurobiol. Dis."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1001\/jamaneurol.2017.3299","article-title":"The Parkinson pandemic\u2014a call to action","volume":"75","author":"Dorsey","year":"2018","journal-title":"JAMA Neurol."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"6838","DOI":"10.1523\/JNEUROSCI.5699-09.2010","article-title":"Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival","volume":"30","author":"Emmanouilidou","year":"2010","journal-title":"J. Neurosci."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1016\/j.molcel.2014.12.025","article-title":"The bacterial curli system possesses a potent and selective inhibitor of amyloid formation","volume":"57","author":"Evans","year":"2015","journal-title":"Mol. Cell"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1016\/S1474-4422(15)00007-1","article-title":"Gastrointestinal dysfunction in Parkinson's disease","volume":"14","author":"Fasano","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"436813","DOI":"10.4061\/2011\/436813","article-title":"Parkinson's disease and systemic","volume":"2011","author":"Ferrari","year":"2011","journal-title":"Inflammation"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1038\/s41434-021-00230-4","article-title":"Liver targeting with rAAV7: balancing tropism with immune profiles","volume":"28","author":"Flotte","year":"2021","journal-title":"Gene Ther."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"28032","DOI":"10.1371\/journal.pone.0028032","article-title":"Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson's disease","volume":"6","author":"Forsyth","year":"2011","journal-title":"PLoS One"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1038\/nbt.1515","article-title":"Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes","volume":"27","author":"Foust","year":"2009","journal-title":"Nat. Biotechnol."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"62143","DOI":"10.1371\/journal.pone.0062143","article-title":"Alpha-synuclein induces lysosomal rupture and cathepsin dependent reactive oxygen species following endocytosis","volume":"8","author":"Freeman","year":"2013","journal-title":"PLoS ONE"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1136\/jnnp.2006.107904","article-title":"G2019s LRRK2 mutation causing Parkinson's disease without Lewy bodies","volume":"78","author":"Gaig","year":"2007","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s12883-018-1034-3","article-title":"A survey of subjective constipation in Parkinson's disease patients in shanghai and literature review","volume":"18","author":"Gan","year":"2018","journal-title":"BMC Neurol."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"702639","DOI":"10.3389\/fnagi.2021.702639","article-title":"Alpha-Synuclein as a biomarker of Parkinson\u2019s disease: good, but not good enough","volume":"13","author":"Ganguly","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/j.it.2008.05.002","article-title":"Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression","volume":"29","author":"Gao","year":"2008","journal-title":"Trends Immunol."},{"key":"ref55","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s13024-024-00756-2","article-title":"\u03b1-Synuclein pathology disrupts mitochondrial function in dopaminergic and cholinergic neurons at-risk in Parkinson's disease","volume":"19","author":"Geibl","year":"2023","journal-title":"Mol. Neurodegen."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.1096\/fj.05-3776fje","article-title":"Exaggerated neuroinflammation and sickness behavior in aged mice after activation of the peripheral innate immune system","volume":"19","author":"Godbout","year":"2005","journal-title":"FASEB J"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"81","DOI":"10.3389\/fnmol.2014.00081","article-title":"Intravenous AAV9 efficiently transduces myenteric neurons in neonate and juvenile mice","volume":"7","author":"Gombash","year":"2014","journal-title":"Front. Mol. Neurosci."},{"key":"ref58","first-page":"473589","article-title":"Altered gut microbiome in Parkinson's disease and the influence of lipopolysaccharide in a human \u03b1-synuclein over-expressing mouse model","author":"Gorecki","year":"2019"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"1058","DOI":"10.1038\/mt.2011.72","article-title":"Preclinical differences of intravascular aav9 delivery to neurons and glia: a comparative study of adult mice and nonhuman primates","volume":"19","author":"Gray","year":"2011","journal-title":"Mol. Ther."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1002\/ana.25557","article-title":"Increased immune activation by pathologic \u03b1-synuclein in Parkinson's disease","volume":"86","author":"Grozdanov","year":"2019","journal-title":"Ann. Neurol."},{"key":"ref61","doi-asserted-by":"publisher","first-page":"4999","DOI":"10.4049\/jimmunol.1402598","article-title":"Lipopolysaccharide regulation of intestinal tight junction permeability is mediated by TLR-4 signal transduction pathway activation of FAK and MyD88","volume":"195","author":"Guo","year":"2015","journal-title":"J. Immunol."},{"key":"ref62","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2019.00093","article-title":"Adeno-associated virus technologies and methods for targeted neuronal manipulation","volume":"93","author":"Haery","year":"2019","journal-title":"Front. Neuroanat."},{"key":"ref63","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1007\/s00401-011-0852-9","article-title":"Neuropathology underlying clinical variability in patients with synucleinopathies","volume":"122","author":"Halliday","year":"2011","journal-title":"Acta Neuropathol."},{"key":"ref64","doi-asserted-by":"publisher","first-page":"6466","DOI":"10.1073\/pnas.81.20.6466","article-title":"Use of adeno-associated virus as a mammalian DNA cloning vector: transduction of neomycin resistance into mammalian tissue culture cells","volume":"81","author":"Hermonat","year":"1984","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref65","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1007\/s00401-013-1214-6","article-title":"Accumulation of \u03b1-synuclein in the bowel of patients in the pre-clinical phase of Parkinson's disease","volume":"127","author":"Hilton","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref66","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1007\/s00401-014-1343-6","article-title":"Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats","volume":"128","author":"Holmqvist","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref67","doi-asserted-by":"publisher","first-page":"111376","DOI":"10.1016\/j.exger.2021.111376","article-title":"Neuroprotective effects of short-chain fatty acids in MPTP induced mice model of Parkinson's disease","volume":"150","author":"Hou","year":"2021","journal-title":"Exp. Gerontol."},{"key":"ref68","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1002\/mds.27326","article-title":"Stool immune profiles evince gastrointestinal inflammation in Parkinson's disease","volume":"33","author":"Houser","year":"2018","journal-title":"Mov. Disord."},{"key":"ref69","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/MD.0000000000016163","article-title":"Fecal microbiota transplantation to treat Parkinson\u2019s disease with constipation: a case report","volume":"98","author":"Huang","year":"2019","journal-title":"Medicine"},{"key":"ref70","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1016\/j.neures.2020.11.004","article-title":"Glial activation precedes alpha-synuclein pathology in a mouse model of Parkinson's disease","volume":"170","author":"Izco","year":"2021","journal-title":"Neurosci. Res."},{"key":"ref71","doi-asserted-by":"publisher","first-page":"e2312306120","DOI":"10.1073\/pnas.2312306120","article-title":"Lysophagy protects against propagation of \u03b1-synuclein aggregation through ruptured lysosomal vesicles","volume":"121","author":"Kakuda","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref72","doi-asserted-by":"publisher","first-page":"13482","DOI":"10.1074\/jbc.M117.780296","article-title":"Selective imaging of internalized proteopathic \u03b1-synuclein seeds in primary neurons reveals mechanistic insight into transmission of synucleinopathies","volume":"292","author":"Karpowicz","year":"2017","journal-title":"J Biol. Chem."},{"key":"ref73","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1002\/mds.25736","article-title":"Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson\u2019s disease","volume":"29","author":"Kelly","year":"2014","journal-title":"Mov. Disord."},{"key":"ref74","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.jocn.2018.10.079","article-title":"Peripheral blood inflammatory markers in early Parkinson's disease","volume":"58","author":"Kim","year":"2018","journal-title":"J. Clin. Neurosci."},{"key":"ref75","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1002\/mds.29056","article-title":"Serum inflammatory markers and progression of nonmotor symptoms in early Parkinson's disease","volume":"37","author":"Kim","year":"2022","journal-title":"Mov. Disord."},{"key":"ref76","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1016\/j.neuron.2019.05.035","article-title":"Transneuronal propagation of pathologic \u03b1-synuclein from the gut to the brain models Parkinson\u2019s disease","volume":"103","author":"Kim","year":"2019","journal-title":"Neuron"},{"key":"ref77","doi-asserted-by":"publisher","first-page":"30891","DOI":"10.1038\/srep30891","article-title":"Exposure to bacterial endotoxin generates a distinct strain of \u03b1-synuclein fibril","volume":"6","author":"Kim","year":"2016","journal-title":"Sci. Rep."},{"key":"ref78","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s13075-019-2018-4","article-title":"A distinct gut microbiota composition in patients with ankylosing spondylitis is associated with increased levels of fecal calprotectin","volume":"21","author":"Klingberg","year":"2019","journal-title":"Arthritis Res. Ther."},{"key":"ref79","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1186\/1750-1326-7-38","article-title":"Suppression of dynamin GTPase decreases \u03b1-synuclein uptake by neuronal and oligodendroglial cells: a potent therapeutic target for synucleinopathy","volume":"7","author":"Konno","year":"2012","journal-title":"Mol. Neurodegener."},{"key":"ref80","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1007\/s00401-003-0705-2","article-title":"Lewy body densities in the entorhinal and anterior cingulate cortex predict cognitive deficits in Parkinson's disease","volume":"106","author":"K\u00f6vari","year":"2003","journal-title":"Acta Neuropathol."},{"key":"ref81","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/s41593-019-0541-x","article-title":"\u03b1-Synuclein strains target distinct brain regions and cell types","volume":"23","author":"Lau","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref82","doi-asserted-by":"publisher","first-page":"1835","DOI":"10.1016\/j.biocel.2008.01.017","article-title":"Assembly-dependent endocytosis and clearance of extracellular alpha-synuclein","volume":"40","author":"Lee","year":"2008","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref83","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1111\/cns.13990","article-title":"Gut bacterial profiles in Parkinson's disease: a systematic review","volume":"29","author":"Li","year":"2023","journal-title":"CNS Neurosci. Ther."},{"key":"ref84","doi-asserted-by":"publisher","first-page":"1137366","DOI":"10.3389\/fmed.2023.1137366","article-title":"Inflammatory bowel disease and risk of Parkinson\u2019s disease: evidence from a meta-analysis of 14 studies involving more than 13.4 million individuals","volume":"10","author":"Li","year":"2023","journal-title":"Front. Med."},{"key":"ref85","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/nature21029","article-title":"Neurotoxic reactive astrocytes are induced by activated microglia","volume":"541","author":"Liddelow","year":"2017","journal-title":"Nature"},{"key":"ref86","doi-asserted-by":"publisher","first-page":"880","DOI":"10.3390\/microorganisms11040880","article-title":"Gut dysbiosis: a target for protective interventions against Parkinson\u2019s disease","volume":"11","author":"Lima","year":"2023","journal-title":"Microorganisms"},{"key":"ref87","doi-asserted-by":"publisher","first-page":"1996","DOI":"10.1212\/WNL.0000000000003961","article-title":"Vagotomy and Parkinson disease: a Swedish register-based matched-cohort study","volume":"88","author":"Liu","year":"2017","journal-title":"Neurology"},{"key":"ref88","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.bbi.2024.01.010","article-title":"Microbiota-microglia crosstalk between Blautia producta and neuroinflammation of Parkinson's disease: a bench-to-bedside translational approach","volume":"117","author":"Liu","year":"2024","journal-title":"Brain Behav. Immun."},{"key":"ref89","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40035-022-00293-2","article-title":"Propagation of tau and \u03b1-synuclein in the brain: therapeutic potential of the glymphatic system","volume":"11","author":"Lopes","year":"2022","journal-title":"Transl. Neurodegeneration"},{"key":"ref90","doi-asserted-by":"publisher","first-page":"6098","DOI":"10.1073\/pnas.0501814102","article-title":"Protein fibrils in nature can enhance amyloid protein a amyloidosis in mice: cross-seeding as a disease mechanism","volume":"102","author":"Lundmark","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref91","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41419-023-06251-8","article-title":"Aggregation of alpha-synuclein disrupts mitochondrial metabolism and induce mitophagy via cardiolipin externalization","volume":"14","author":"Lurette","year":"2023","journal-title":"Cell Death Disease"},{"key":"ref92","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1093\/braincomms\/fcab247","article-title":"Viral alpha-synuclein knockdown prevents spreading synucleinopathy","volume":"3","author":"Menon","year":"2021","journal-title":"Brain Communications"},{"key":"ref93","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.4103\/1673-5374.308089","article-title":"Short-chain fatty acids in the context of Parkinson\u2019s disease","volume":"16","author":"Metzdorf","year":"2021","journal-title":"Neural Reg. Res."},{"key":"ref94","doi-asserted-by":"publisher","first-page":"638867","DOI":"10.3389\/fimmu.2021.638867","article-title":"Microbiome or infections: amyloid-containing biofilms as a trigger for complex human diseases","volume":"12","author":"Miller","year":"2021","journal-title":"Front. Immunol."},{"key":"ref95","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1182\/blood-2013-01-306647","article-title":"Immune responses to AAV vectors: overcoming barriers to successful gene therapy","volume":"122","author":"Mingozzi","year":"2013","journal-title":"Blood"},{"key":"ref96","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/0304-3940(94)90508-8","article-title":"Interleukin-1\u03b2, interleukin-6, epidermal growth factor and transforming growth factor-\u03b1 are elevated in the brain from parkinsonian patients","volume":"180","author":"Mogi","year":"1994","journal-title":"Neuro Lett"},{"key":"ref97","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1097\/01.jnen.0000230520.47768.1a","article-title":"Relationship among \u03b1-synuclein accumulation, dopamine synthesis, and neurodegeneration in Parkinson disease substantia nigra","volume":"65","author":"Mori","year":"2006","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref98","doi-asserted-by":"publisher","first-page":"680","DOI":"10.3389\/fimmu.2014.00680","article-title":"Innate immune programing by endotoxin and its pathological consequences","volume":"6","author":"Morris","year":"2015","journal-title":"Front. Immunol."},{"key":"ref99","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1097\/NEN.0b013e3182801cde","article-title":"Alpha-synuclein pathology and axonal degeneration of the peripheral motor nerves innervating pharyngeal muscles in Parkinson disease","volume":"72","author":"Mu","year":"2013","journal-title":"J. Neurol. Exp."},{"key":"ref100","doi-asserted-by":"publisher","first-page":"992","DOI":"10.3389\/fnins.2019.00992","article-title":"Fecal calprotectin as a marker of the gut immune system activation is elevated in Parkinson's disease","volume":"13","author":"Mulak","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref101","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s40035-019-0165-9","article-title":"The interplay of aging, genetics and environmental factors in the pathogenesis of Parkinson's disease","volume":"8","author":"Pang","year":"2019","journal-title":"Transl. Neurodegener."},{"key":"ref102","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1007\/s00401-008-0346-6","article-title":"Applicability of current staging\/categorization of \u03b1-synuclein pathology and their clinical relevance","volume":"115","author":"Parkkinen","year":"2008","journal-title":"Acta Neuropathol."},{"key":"ref103","first-page":"304","article-title":"Widespread and abundant alpha-synuclein pathology in a neurologically unimpaired subject","author":"Parkkinen","year":"2005"},{"key":"ref104","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1038\/nature14547","article-title":"\u03b1-Synuclein strains cause distinct synucleinopathies after local and systemic administration","volume":"522","author":"Peelaerts","year":"2015","journal-title":"Nature"},{"key":"ref105","first-page":"829","article-title":"Role of TLR4 in the gut-brain axis in Parkinson\u2019s disease: a translational study from men to mice","author":"Perez-Pardo","year":"2019"},{"key":"ref106","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1038\/nri2015","article-title":"Systemic infections and inflammation affect chronic neurodegeneration","volume":"7","author":"Perry","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref107","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1002\/glia.440070111","article-title":"Altered antigen expression of microglia in the aged rodent CNS","volume":"7","author":"Perry","year":"1993","journal-title":"Glia"},{"key":"ref108","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1001\/jamaneurol.2018.0605","article-title":"Anti-tumor necrosis factor therapy and incidence of Parkinson disease among patients with inflammatory bowel disease","volume":"75","author":"Peter","year":"2018","journal-title":"JAMA Neurol."},{"key":"ref109","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3390\/cells10092229","article-title":"\u0391-synuclein decreases the abundance of proteasome subunits and alters ubiquitin conjugates in yeast","volume":"10","author":"Popova","year":"2021","journal-title":"Cells"},{"key":"ref110","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1038\/nrneurol.2016.152","article-title":"Advances in markers of prodromal Parkinson disease","volume":"12","author":"Postuma","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"ref111","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1002\/glia.20467","article-title":"Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration","volume":"55","author":"Qin","year":"2007","journal-title":"Glia"},{"key":"ref112","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.1093\/brain\/awab440","article-title":"Differentially targeted seeding reveals unique pathological alpha-synuclein propagation patterns","volume":"145","author":"Rahayel","year":"2022","journal-title":"Brain"},{"key":"ref113","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41531-023-00578-x","article-title":"Alpha synuclein modulates mitochondrial Ca2+ uptake from ER during cell stimulation and under stress conditions","volume":"9","author":"Ramezani","year":"2023","journal-title":"NPJ Parkinson's Disease"},{"key":"ref114","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1038\/s41592-020-0799-7","article-title":"Multiplexed Cre-dependent selection yields systemic AAVs for targeting distinct brain cell types","volume":"17","author":"Ravindra Kumar","year":"2020","journal-title":"Nat. Methods"},{"key":"ref115","doi-asserted-by":"publisher","first-page":"189","DOI":"10.3389\/fcimb.2016.00189","article-title":"Expression of curli by Escherichia coli O157: H7 strains isolated from patients during outbreaks is different from similar strains isolated from leafy green production environments","volume":"6","author":"Ravva","year":"2016","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref116","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1111\/j.1471-4159.2007.04567.x","article-title":"Blood\u2013brain barrier disruption induces in vivo degeneration of nigral dopaminergic neurons","volume":"101","author":"Rite","year":"2007","journal-title":"J. Neurochem."},{"key":"ref117","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.brainres.2007.11.015","article-title":"Specific AAV serotypes stably transduce primary hippocampal and cortical cultures with high efficiency and low toxicity","volume":"1190","author":"Royo","year":"2008","journal-title":"Brain Res."},{"key":"ref118","doi-asserted-by":"publisher","first-page":"917797","DOI":"10.3389\/fnagi.2022.917797","article-title":"Age-related midbrain inflammation and senescence in Parkinson\u2019s disease","volume":"14","author":"Russo","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"ref119","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1016\/0024-3205(95)00008-t","article-title":"Systemic cytokine administration can affect blood-brain barrier permeability in the rat","volume":"56","author":"Saija","year":"1995","journal-title":"Life Sci."},{"key":"ref120","first-page":"1469","article-title":"Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease","author":"Sampson","year":"2016"},{"key":"ref121","doi-asserted-by":"publisher","first-page":"4374","DOI":"10.1074\/jbc.M115.705095","article-title":"Effects of serine 129 phosphorylation on \u03b1-Synuclein aggregation, membrane association, and internalization","volume":"291","author":"Samuel","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref122","doi-asserted-by":"publisher","first-page":"e3001287","DOI":"10.1371\/journal.pbio.3001287","article-title":"\u03b1-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes","volume":"19","author":"Senol","year":"2021","journal-title":"PLoS Biol."},{"key":"ref123","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0197-4580(97)00168-1","article-title":"Microglial expression of MHC class II increases in normal aging of nonhuman primates","volume":"19","author":"Sheffield","year":"1998","journal-title":"Neuro Biol. Aging"},{"key":"ref124","doi-asserted-by":"publisher","first-page":"1629","DOI":"10.1097\/00001756-199508000-00010","article-title":"Nitric oxide modulates blood-brain barrier permeability during infections with an inactivated bacterium","volume":"6","author":"Shukla","year":"1995","journal-title":"Neuroreport"},{"key":"ref125","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1096\/fj.03-1112rev","article-title":"Does \u03b1-synuclein modulate dopaminergic synaptic content and tone at the synapse?","volume":"18","author":"Sidhu","year":"2004","journal-title":"FASEB J."},{"key":"ref126","doi-asserted-by":"publisher","first-page":"1012517","DOI":"10.1371\/journal.ppat.1012517","article-title":"\u03b1-Synuclein strain propagation is independent of cellular prion protein expression in a transgenic synucleinopathy mouse model","volume":"20","author":"So","year":"2024","journal-title":"PLoS Pathog."},{"key":"ref127","volume-title":"Neuroanatomy, substantia Nigra","author":"Sonne","year":"2022"},{"key":"ref128","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.bbi.2018.02.005","article-title":"Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson's disease mice: gut microbiota, glial reaction and TLR4\/TNF-\u03b1 signaling pathway","volume":"70","author":"Sun","year":"2018","journal-title":"Brain Behav. Immun."},{"key":"ref129","doi-asserted-by":"publisher","first-page":"27441","DOI":"10.1074\/jbc.M101318200","article-title":"Induction of neuronal cell death by Rab5A-dependent endocytosis of alpha-synuclein","volume":"276","author":"Sung","year":"2001","journal-title":"J Biol. Chem."},{"key":"ref130","doi-asserted-by":"publisher","first-page":"7","DOI":"10.14802\/jmd.14002","article-title":"The frequency and severity of gastrointestinal symptoms in patients with early Parkinson\u2019s disease","volume":"7","author":"Sung","year":"2014","journal-title":"J. Movem. Disorders"},{"key":"ref131","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1002\/ana.24448","article-title":"Vagotomy and subsequent risk of Parkinson's disease","volume":"78","author":"Svensson","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref132","first-page":"5","article-title":"Toll-like receptor 4 (TLR4) antagonists as potential therapeutics for intestinal inflammation","author":"Tam","year":"2021"},{"key":"ref133","first-page":"546","volume-title":"Gut microbial ecosystem in Parkinson disease: New Clinicobiological insights from multi-omics","author":"Tan","year":"2021"},{"key":"ref134","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1038\/s41582-022-00681-2","article-title":"The microbiome-gut-brain axis in Parkinson disease - from basic research to the clinic","volume":"18","author":"Tan","year":"2022","journal-title":"Nat. Rev. Neurol."},{"key":"ref135","doi-asserted-by":"publisher","first-page":"18675","DOI":"10.1074\/jbc.M116.734707","article-title":"The effect of fragmented pathogenic \u03b1-synuclein seeds on prion-like propagation","volume":"291","author":"Tarutani","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref136","first-page":"455","article-title":"Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction","author":"Thevaranjan","year":"2017"},{"key":"ref137","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.1089\/hum.2012.013","article-title":"Targeted delivery of self-complementary adeno-associated virus serotype 9 to the brain, using magnetic resonance imaging-guided focused ultrasound","volume":"23","author":"Th\u00e9venot","year":"2012","journal-title":"Hum. Gene Ther."},{"key":"ref138","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1371\/journal.pone.0094944","article-title":"Delirium and high fever are associated with subacute motor deterioration in Parkinson disease: a nested case-control study","volume":"9","author":"Umemura","year":"2014","journal-title":"PLoS One"},{"key":"ref139","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.parkreldis.2016.08.019","article-title":"Short chain fatty acids and gut microbiota differ between patients with Parkinson's disease and age-matched controls","volume":"32","author":"Unger","year":"2016","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref140","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1007\/s00401-019-02040-w","article-title":"Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats","volume":"138","author":"Van Den Berge","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref141","doi-asserted-by":"publisher","first-page":"1853","DOI":"10.1093\/brain\/awab061","article-title":"Ageing promotes pathological alpha-synuclein propagation and autonomic dysfunction in wild-type rats","volume":"144","author":"Van Den Berge","year":"2021","journal-title":"Brain"},{"key":"ref142","doi-asserted-by":"publisher","first-page":"32486","DOI":"10.1074\/jbc.M110.139576","article-title":"Membrane curvature induction and tubulation are common features of synucleins and apolipoproteins","volume":"285","author":"Varkey","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref143","first-page":"219","article-title":"Pentosan polysulfate protects brain endothelial cells against bacterial lipopolysaccharide-induced damages","author":"Veszelka","year":"2007"},{"key":"ref144","doi-asserted-by":"publisher","first-page":"1687","DOI":"10.1111\/j.1471-4159.2010.06879.x","article-title":"Ulcerative colitis exacerbates lipopolysaccharide-induced damage to the nigral dopaminergic system: potential risk factor in Parkinson\u2019s disease","volume":"114","author":"Villar\u00e1n","year":"2010","journal-title":"J. Neurochem."},{"key":"ref145","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1212\/WNL.0000000000001240","article-title":"Colonic mucosal a-synuclein lacks specificity as a biomarker for Parkinson disease","volume":"84","author":"Visanji","year":"2015","journal-title":"Neurology"},{"key":"ref146","first-page":"4595","article-title":"Vesicle permeabilization by protofibrillar \u03b1-synuclein is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanism","author":"Volles","year":"2002"},{"key":"ref147","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1097\/01.wnr.0000215769.71657.65","article-title":"Expression levels of vascular endothelial growth factor and its receptors in Parkinson's disease","volume":"17","author":"Wada","year":"2006","journal-title":"Neuroreport"},{"key":"ref148","doi-asserted-by":"publisher","first-page":"S92","DOI":"10.1016\/j.parkreldis.2006.05.028","article-title":"Progression patterns of neuronal loss and Lewy body pathology in the substantia nigra in Parkinson's disease","volume":"12","author":"Wakabayashi","year":"2006","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref149","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1007\/BF00294234","article-title":"Parkinson's disease: an immunohistochemical study of Lewy body-containing neurons in the enteric nervous system","volume":"79","author":"Wakabayashi","year":"1990","journal-title":"Acta Neuropathol."},{"key":"ref150","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1007\/BF00687767","article-title":"Parkinson's disease: the presence of Lewy bodies in Auerbach's and Meissner's plexuses","volume":"76","author":"Wakabayashi","year":"1988","journal-title":"Acta Neuropathol."},{"key":"ref151","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1679\/aohc.52.Suppl_191","article-title":"Lewy bodies in the enteric nervous system in Parkinson's disease","volume":"52","author":"Wakabayashi","year":"1989","journal-title":"Arch. Histol. Cytol."},{"key":"ref152","doi-asserted-by":"publisher","first-page":"167161","DOI":"10.3389\/fnins.2015.00433","article-title":"Alpha-synuclein toxicity in the early secretory pathway: how it drives neurodegeneration in parkinsons disease","volume":"9","author":"Wang","year":"2015","journal-title":"Front. Neurosci."},{"key":"ref153","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.parkreldis.2022.06.004","article-title":"Biofluid markers of blood-brain barrier disruption and neurodegeneration in Lewy body spectrum diseases: a systematic review and meta-analysis","volume":"101","author":"Wong","year":"2022","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref154","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1089\/ars.2005.7.654","article-title":"The role of microglia in paraquat-induced dopaminergic neurotoxicity","volume":"7","author":"Wu","year":"2005","journal-title":"Antioxid. Redox Signal."},{"key":"ref155","first-page":"1","article-title":"Serum short-chain fatty acids and its correlation with motor and non-motor symptoms in Parkinson\u2019s disease patients","volume":"22","author":"Wu","year":"2022","journal-title":"BioMed Central Ltd"},{"key":"ref156","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1002\/mds.101","article-title":"Noninvasive delivery of an \u03b1-synuclein gene silencing vector with magnetic resonance\u2013guided focused ultrasound","volume":"33","author":"Xhima","year":"2018","journal-title":"Mov. Disord."},{"key":"ref157","doi-asserted-by":"publisher","first-page":"e22035","DOI":"10.1097\/MD.0000000000022035","article-title":"Fecal microbiota transplantation therapy for Parkinson's disease: a preliminary study","volume":"99","author":"Xue","year":"2020","journal-title":"Medicine"},{"key":"ref158","first-page":"743","article-title":"Brain and systemic inflammation in de novo Parkinson's disease","author":"Yacoubian","year":"2023"},{"key":"ref159","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/s13024-018-0241-0","article-title":"Extracellular \u03b1-synuclein levels are regulated by neuronal activity","volume":"13","author":"Yamada","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"ref160","doi-asserted-by":"publisher","first-page":"1068","DOI":"10.1161\/STROKEAHA.115.010835","article-title":"Vascular cell senescence contributes to blood-brain barrier breakdown","volume":"47","author":"Yamazaki","year":"2016","journal-title":"Stroke"},{"key":"ref161","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/s41531-020-0117-1","article-title":"Current and projected future economic burden of Parkinson\u2019s disease in the U.S.","volume":"6","author":"Yang","year":"2020","journal-title":"NPJ Parkinsons Dis."},{"key":"ref162","doi-asserted-by":"publisher","first-page":"16790","DOI":"10.1038\/s41598-017-16790-8","article-title":"Parkinson disease with constipation: clinical features and relevant factors","volume":"8","author":"Yu","year":"2018","journal-title":"Sci. Rep."},{"key":"ref163","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40035-023-00392-8","article-title":"Parkinson\u2019s disease and gut microbiota: from clinical to mechanistic and therapeutic studies","volume":"12","author":"Zhang","year":"2023","journal-title":"Transl. Neurodegener."},{"key":"ref164","first-page":"533","volume-title":"Aggregated \u03b1-synuclein activates microglia: a process leading to disease progression in Parkinson's disease","author":"Zhang","year":"2005"},{"key":"ref165","doi-asserted-by":"publisher","first-page":"147749","DOI":"10.1016\/j.brainres.2021.147749","article-title":"Sodium butyrate attenuates rotenone-induced toxicity by activation of autophagy through epigenetically regulating PGC-1\u03b1 expression in PC12 cells","volume":"1776","author":"Zhang","year":"2022","journal-title":"Brain Res."},{"key":"ref166","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12974-023-02846-2","article-title":"Lipopolysaccharide-binding protein and future Parkinson\u2019s disease risk: a European prospective cohort","volume":"22","author":"Zhao","year":"2023","journal-title":"BioMed Central Ltd"},{"key":"ref167","doi-asserted-by":"publisher","first-page":"344","DOI":"10.4103\/1673-5374.317981","article-title":"Association between inflammatory bowel diseases and Parkinson's disease: systematic review and meta-analysis","volume":"17","author":"Zhu","year":"2022","journal-title":"Neural Regen. Res."},{"key":"ref168","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1038\/mt.2008.76","article-title":"Analysis of AAV serotypes 1-9 mediated gene expression and tropism in mice after systemic injection","volume":"16","author":"Zincarelli","year":"2008","journal-title":"Mol. Ther."},{"key":"ref169","doi-asserted-by":"publisher","first-page":"184040","DOI":"10.1371\/journal.pone.0184040","article-title":"Proteasome impairment by \u03b1-synuclein","volume":"12","author":"Zondler","year":"2017","journal-title":"PLoS One"}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2025.1600782\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T05:28:30Z","timestamp":1759987710000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2025.1600782\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,9]]},"references-count":169,"alternative-id":["10.3389\/fnagi.2025.1600782"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2025.1600782","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,9]]},"article-number":"1600782"}}