{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T18:54:14Z","timestamp":1785783254655,"version":"3.56.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T00:00:00Z","timestamp":1606953600000},"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. Cell Dev. Biol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Diabetes increases the risk of Parkinson\u2019s disease (PD). The phosphorylation of type 1 insulin receptor substrate (IRS-1) determines the function of insulin signaling pathway. Extracellular vesicles (EVs) are emerging as biomarkers of human diseases. The present study investigated whether PD patients exert altered phosphorylation IRS-1 (p-IRS-1) inside the blood neuron-derived extracellular vesicles (NDEVs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Research Design and Methods<\/jats:title><jats:p>In total, there were 94 patients with PD and 63 healthy controls recruited and their clinical manifestations were evaluated. Blood NDEVs were isolated using the immunoprecipitation method, and Western blot analysis was conducted to assess total IRS-1, p-IRS-1, and downstream substrates level in blood NDEVs. Statistical analysis was performed using SPSS 19.0, and <jats:italic>p<\/jats:italic> &amp;lt; 0.05 was considered significant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The isolated blood EVs were validated according to the presence of CD63 and HSP70, nanoparticle tracking analysis and transmission electron microscopy. NDEVs were positive with neuronal markers. PD patients exerted significantly higher level of p-IRS-1<jats:sup>S312<\/jats:sup> in blood NDEVs than controls. In addition, the p-IRS-1<jats:sup>S312<\/jats:sup> levels in blood NDEVs was positively associated with the severity of tremor in PD patients after adjusting of age, sex, hemoglobin A1c, and body mass index (BMI).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>PD patients exerted altered p-IRS-1<jats:sup>S312<\/jats:sup> in the blood NDEVs, and also correlated with the severity of tremor. These findings suggested the association between dysfunctional insulin signaling pathway with PD. The role of altered p-IRS-1<jats:sup>S312<\/jats:sup> in blood NDEVs as a segregating biomarker of PD required further cohort study to assess the association with the progression of PD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcell.2020.564641","type":"journal-article","created":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T08:26:50Z","timestamp":1606984010000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":37,"title":["Altered Insulin Receptor Substrate 1 Phosphorylation in Blood Neuron-Derived Extracellular Vesicles From Patients With Parkinson\u2019s Disease"],"prefix":"10.3389","volume":"8","author":[{"given":"Szu-Yi","family":"Chou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lung","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Chih","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Yuan","family":"Chiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Chen","family":"Hsieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Tai","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2020,12,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1038\/nrneurol.2017.185","article-title":"Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums.","volume":"14","author":"Arnold","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1001\/jamaneurol.2018.4304","article-title":"Utility of neuronal-derived exosomes to examine molecular mechanisms that affect motor function in patients with parkinson disease: a secondary analysis of the exenatide-PD trial.","volume":"76","author":"Athauda","year":"2019","journal-title":"JAMA Neurol."},{"key":"B3","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1016\/S0140-6736(17)31585-4","article-title":"Exenatide once weekly versus placebo in Parkinson\u2019s disease: a randomised, double-blind, placebo-controlled trial.","volume":"390","author":"Athauda","year":"2017","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.1002\/mds.27087","article-title":"Brain insulin resistance in Parkinson\u2019s disease.","volume":"32","author":"Bassil","year":"2017","journal-title":"Move. Disorders"},{"key":"B5","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1016\/j.nbd.2011.09.009","article-title":"High-fat diet exacerbates MPTP-induced dopaminergic degeneration in mice.","volume":"45","author":"Bousquet","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"B6","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1038\/nrn.2015.29","article-title":"Extracellular vesicles round off communication in the nervous system.","volume":"17","author":"Budnik","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.1212\/wnl.0b013e3182553cc9","article-title":"Clinical features of Parkinson disease when onset of diabetes came first. A case-control study.","volume":"78","author":"Cereda","year":"2012","journal-title":"Neurology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2614","DOI":"10.2337\/dc11-1584","article-title":"Diabetes and risk of Parkinson\u2019s disease: a systematic review and meta-analysis.","volume":"34","author":"Cereda","year":"2011","journal-title":"Diabetes Care"},{"key":"B9","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.cmet.2009.11.003","article-title":"Irs1 serine 307 promotes insulin sensitivity in mice.","volume":"11","author":"Copps","year":"2010","journal-title":"Cell Metab."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2565","DOI":"10.1007\/s00125-012-2644-8","article-title":"Regulation of insulin sensitivity by serine\/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2.","volume":"55","author":"Copps","year":"2012","journal-title":"Diabetologia"},{"key":"B11","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1046\/j.1471-4159.2003.02210.x","article-title":"Protection by pioglitazone in the MPTP model of Parkinson\u2019s disease correlates with I\u03baB\u03b1 induction and block of NF\u03baB and iNOS activation.","volume":"88","author":"Dehmer","year":"2004","journal-title":"J. Neurochem."},{"key":"B12","article-title":"Pancreatic islet function tests","author":"Desimone","year":"2000","journal-title":"Endotext, \u00a9 2000-2020"},{"key":"B13","doi-asserted-by":"crossref","DOI":"10.1016\/j.jalz.2014.06.008","article-title":"Identification of preclinical Alzheimer\u2019s disease by a profile of pathogenic proteins in neurally derived blood exosomes: a case-control study.","volume":"11","author":"Fiandaca","year":"2015","journal-title":"Alzheimers Dement."},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2019.00452","article-title":"Neuron-derived exosome proteins may contribute to progression from repetitive mild traumatic brain injuries to chronic traumatic encephalopathy.","volume":"13","author":"Goetzl","year":"2019","journal-title":"Front. Neurosci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"3992","DOI":"10.2337\/db14-0340","article-title":"Insulin regulates brain function, but how does it get there?","volume":"63","author":"Gray","year":"2014","journal-title":"Diabetes"},{"key":"B16","doi-asserted-by":"publisher","first-page":"8199","DOI":"10.1074\/jbc.m209153200","article-title":"Modulation of insulin-stimulated degradation of human insulin receptor Substrate-1 by Serine 312 phosphorylation.","volume":"278","author":"Greene","year":"2003","journal-title":"J. Biol. Chem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.biochi.2004.10.019","article-title":"Positive and negative regulation of insulin signaling through IRS-1 phosphorylation.","volume":"87","author":"Gual","year":"2005","journal-title":"Biochimie"},{"key":"B18","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/nrm.2017.89","article-title":"Biochemical and cellular properties of insulin receptor signalling.","volume":"19","author":"Haeusler","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B19","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1007\/s00109-019-01810-z","article-title":"Exosomes from patients with Parkinson\u2019s disease are pathological in mice.","volume":"97","author":"Han","year":"2019","journal-title":"J. Mol. Med."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3390\/cells9030740","article-title":"Insulin resistance promotes Parkinson\u2019s disease through aberrant expression of \u03b1-synuclein, mitochondrial dysfunction, and deregulation of the polo-like kinase 2 signaling.","volume":"9","author":"Hong","year":"2020","journal-title":"Cells"},{"key":"B21","doi-asserted-by":"crossref","first-page":"842","DOI":"10.2337\/dc06-2011","article-title":"Type 2 diabetes and the risk of Parkinson\u2019s disease.","volume":"30","author":"Hu","year":"2007","journal-title":"Diabetes Care"},{"key":"B22","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1136\/jnnp.55.3.181","article-title":"Accuracy of clinical diagnosis of idiopathic Parkinson\u2019s disease: a clinico-pathological study of 100 cases.","volume":"55","author":"Hughes","year":"1992","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"B23","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.taap.2016.03.004","article-title":"Metformin, besides exhibiting strong in vivo anti-inflammatory properties, increases mptp-induced damage to the nigrostriatal dopaminergic system.","volume":"298","author":"Ismaiel","year":"2016","journal-title":"Toxicol, Appl. Pharmacol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1096\/fj.14-262048","article-title":"Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer\u2019s disease.","volume":"29","author":"Kapogiannis","year":"2015","journal-title":"FASEB J."},{"key":"B25","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1016\/j.neuropharm.2017.08.015","article-title":"Metformin lowers \u03b1-synuclein phosphorylation and upregulates neurotrophic factor in the MPTP mouse model of Parkinson\u2019s disease.","volume":"125","author":"Katila","year":"2017","journal-title":"Neuropharmacology"},{"key":"B26","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1016\/j.parkreldis.2013.01.016","article-title":"Diabetes is associated with postural instability and gait difficulty in Parkinson disease.","volume":"19","author":"Kotagal","year":"2013","journal-title":"Parkinson. Related Disord."},{"key":"B27","doi-asserted-by":"publisher","first-page":"588","DOI":"10.2337\/diacare.24.3.588","article-title":"Recent advances in our understanding of insulin action and insulin resistance.","volume":"24","author":"Le Roith","year":"2001","journal-title":"Diabetes Care"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20071728","article-title":"Extracellular vesicle as a source of Alzheimer\u2019s biomarkers: opportunities and challenges.","volume":"20","author":"Lee","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1136\/jnnp.2003.033530","article-title":"Heterogeneity of Parkinson\u2019s disease in the early clinical stages using a data driven approach.","volume":"76","author":"Lewis","year":"2005","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0085781","article-title":"Diabetes and risk of Parkinson\u2019s disease: an updated meta-analysis of case-control studies.","volume":"9","author":"Lu","year":"2014","journal-title":"PLoS One"},{"key":"B31","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.tem.2020.01.007","article-title":"Chronic diabetes complications: the need to move beyond classical concepts.","volume":"31","author":"Mauricio","year":"2020","journal-title":"Trends Endocrinol. Metab."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1933","DOI":"10.1002\/hbm.23494","article-title":"Exosomal biomarkers of brain insulin resistance associated with regional atrophy in Alzheimer\u2019s disease.","volume":"38","author":"Mullins","year":"2017","journal-title":"Hum. Brain Mapp."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2017.00278","article-title":"Plasma extracellular vesicles enriched for neuronal origin: a potential window into brain pathologic processes.","volume":"11","author":"Mustapic","year":"2017","journal-title":"Front. Neurosci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1016\/s1474-4422(15)00144-1","article-title":"Pioglitazone in early Parkinson\u2019s disease: a phase 2, multicentre, double-blind, randomised trial.","volume":"14","year":"2015","journal-title":"Lancet Neurol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1111\/ene.14208","article-title":"A longitudinal study on \u03b1-synuclein in plasma neuronal exosomes as a biomarker for Parkinson\u2019s disease development and progression.","volume":"27","author":"Niu","year":"2020","journal-title":"Eur. J. Neurol."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2013.0516","article-title":"Extracellular vesicles as modulators of cell-to-cell communication in the healthy and diseased brain.","volume":"369","author":"Pegtel","year":"2014","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1080\/08923973.2019.1650371","article-title":"The multiple roles of exosomes in Parkinson\u2019s disease: an overview.","volume":"41","author":"Porro","year":"2019","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1038\/bjp.2008.78","article-title":"The PPAR\u03b3 agonist pioglitazone is effective in the MPTP mouse model of Parkinson\u2019s disease through inhibition of monoamine oxidase B.","volume":"154","author":"Quinn","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"958","DOI":"10.1056\/nejmra1704286","article-title":"Circulating extracellular vesicles in human disease.","volume":"379","author":"Shah","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"B40","doi-asserted-by":"crossref","DOI":"10.1155\/2017\/5952149","article-title":"Accumulation of \u03b1-Synuclein in cerebellar purkinje cells of diabetic rats and its potential relationship with inflammation and oxidative stress markers.","volume":"2017","author":"Solmaz","year":"2017","journal-title":"Neurol. Res. Int."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.2337\/dc11-1511","article-title":"Risk of Parkinson disease onset in patients with diabetes. A 9-year population-based cohort study with age and sex stratifications.","volume":"35","author":"Sun","year":"2012","journal-title":"Diabetes Care"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1316","DOI":"10.1172\/jci59903","article-title":"Demonstrated brain insulin resistance in Alzheimer\u2019s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline.","volume":"122","author":"Talbot","year":"2012","journal-title":"J. Clin. Invest."},{"key":"B43","article-title":"Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the international society for extracellular vesicles and update of the MISEV2014 guidelines.","volume":"7","author":"Th\u00e9ry","year":"2018","journal-title":"J. Extracell. Ves."},{"key":"B44","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1097\/wco.0000000000000384","article-title":"Clinical subtypes and genetic heterogeneity: of lumping and splitting in Parkinson disease.","volume":"29","author":"von Coelln","year":"2016","journal-title":"Curr. Opin. Neurol."},{"key":"B45","doi-asserted-by":"crossref","DOI":"10.1186\/s13024-019-0317-5","article-title":"Neuronally derived extracellular vesicles: an emerging tool for understanding Alzheimer\u2019s disease.","volume":"14","author":"Watson","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"B46","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1093\/brain\/aws360","article-title":"The cerebellum in Parkinson\u2019s disease.","volume":"136","author":"Wu","year":"2013","journal-title":"Brain"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1080\/20013078.2018.1440131","article-title":"Extracellular vesicles as a platform for membrane-associated therapeutic protein delivery.","volume":"7","author":"Yang","year":"2018","journal-title":"J. Extracell. Vesicles"},{"key":"B48","doi-asserted-by":"publisher","first-page":"8152","DOI":"10.1002\/jcp.27603","article-title":"Insulin resistance: Review of the underlying molecular mechanisms.","volume":"234","author":"Yaribeygi","year":"2019","journal-title":"J. Cell Physiol."},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.00086","article-title":"Potential roles of exosomes in Parkinson\u2019s disease: from pathogenesis, diagnosis, and treatment to prognosis.","volume":"8","author":"Yu","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1016\/s0962-8924(01)81297-6","article-title":"Insulin resistance: a phosphorylation-based uncoupling of insulin signaling.","volume":"11","author":"Zick","year":"2001","journal-title":"Trends Cell Biol."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2020.564641\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T08:26:53Z","timestamp":1606984013000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2020.564641\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,3]]},"references-count":50,"alternative-id":["10.3389\/fcell.2020.564641"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2020.564641","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,3]]},"article-number":"564641"}}