{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:40:54Z","timestamp":1785436854270,"version":"3.56.0"},"posted":{"date-parts":[[2025,9,17]]},"group-title":"Neuroscience","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T00:00:00Z","timestamp":1758067200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R35GM142368"],"award-info":[{"award-number":["R35GM142368"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]},{"award":["PD240020"],"award-info":[{"award-number":["PD240020"]}],"id":[{"id":"https:\/\/ror.org\/03g2zjp07","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,9,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Traumatic brain injury (TBI) increases the risk of Parkinson\u2019s disease (PD) development later in life, but much remains unknown regarding the mechanisms driving this relationship. A single, mild brain injury triggers resident and peripheral neuroinflammatory pathways that are similarly activated in PD patients, which could possibly increase susceptibility to neurodegeneration. In this study, we used preclinical mouse models of mild TBI (mTBI) and PD to evaluate how injury-induced immune signaling may exacerbate PD-associated pathologies. Dopaminergic (DA) neurons showed upregulation of genes associated with neuroinflammation, adaptive immunity, and PD following mTBI. mTBI caused degeneration of DA neurons in the substantia nigra (SN) and increased the spread of Lewy body (LB) pathology to other brain regions, such as the ipsilateral cortex, in a preclinical model of PD. Reducing adaptive immune infiltration into the central nervous system (CNS) with a transgenic model lacking mature lymphocytes, or directly by\n                  <jats:italic>in vivo<\/jats:italic>\n                  depletion of T cells or B cells individually, improved neurodegenerative outcomes of DA neurons following brain injury. Our results indicate the possibility of a sustained, chronic peripheral immune cell infiltration which negatively affects both DA neurons and alpha synuclein (\u03b1-syn) fibril propagation, providing insight on therapeutic windows to reduce DA neuron vulnerability.\n                <\/jats:p>","DOI":"10.1101\/2025.09.16.676659","type":"posted-content","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T22:20:15Z","timestamp":1758147615000},"source":"Crossref","is-referenced-by-count":0,"title":["Brain injury contributes to dopaminergic neurodegeneration, Lewy body pathology, and Parkinsonism preclinically with outcomes altered by T cell modulation"],"prefix":"10.64898","author":[{"given":"Colin","family":"Kelly","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia P.","family":"Milner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brooke A.","family":"Lester","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Brindley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyann","family":"Hernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahitya Ranjan","family":"Biswas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Murdaugh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoran","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle L.","family":"Olsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew W.","family":"Buczynski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8470-6056","authenticated-orcid":false,"given":"Alicia M.","family":"Pickrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025092202451741000_2025.09.16.676659v1.1","unstructured":"Georges A , Das JM : Traumatic Brain Injury. IN: StatePearls 2023."},{"key":"2025092202451741000_2025.09.16.676659v1.2","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1001\/jamaneurol.2014.3558","article-title":"Inflammation and neuroprotection in traumatic brain injury","volume":"72","year":"2015","journal-title":"JAMA Neurol"},{"key":"2025092202451741000_2025.09.16.676659v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)01419-8"},{"key":"2025092202451741000_2025.09.16.676659v1.4","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2019.22360"},{"key":"2025092202451741000_2025.09.16.676659v1.5","doi-asserted-by":"crossref","unstructured":"Calabresi P , Mechelli A , Natale G , Volpicelli-Daley L , Di Lazzaro G , Ghiglieri V : Alpha- synuclein in Parkinson\u2019s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction. Cell Death Dis 2023, 14:176.","DOI":"10.1038\/s41419-023-05672-9"},{"key":"2025092202451741000_2025.09.16.676659v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.08.033"},{"key":"2025092202451741000_2025.09.16.676659v1.7","doi-asserted-by":"crossref","unstructured":"Grotewold N , Albin RL : Update: Protective and risk factors for Parkinson disease. Parkinsonism Relat Disord 2024, 125:107026.","DOI":"10.1016\/j.parkreldis.2024.107026"},{"key":"2025092202451741000_2025.09.16.676659v1.8","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000005522"},{"key":"2025092202451741000_2025.09.16.676659v1.9","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1002\/mds.29457","article-title":"Lifelong Association of Disorders Related to Military Trauma with Subsequent Parkinson\u2019s Disease","volume":"38","year":"2023","journal-title":"Mov Disord"},{"key":"2025092202451741000_2025.09.16.676659v1.10","doi-asserted-by":"publisher","DOI":"10.1172\/JCI36470"},{"key":"2025092202451741000_2025.09.16.676659v1.11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02122"},{"key":"2025092202451741000_2025.09.16.676659v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2006.12.003"},{"key":"2025092202451741000_2025.09.16.676659v1.13","doi-asserted-by":"crossref","unstructured":"Yan Z , Yang W , Wei H , Dean MN , Standaert DG , Cutter GR , Benveniste EN , Qin H : Dysregulation of the Adaptive Immune System in Patients With Early-Stage Parkinson Disease. Neurol Neuroimmunol Neuroinflamm 2021, 8.","DOI":"10.1212\/NXI.0000000000001036"},{"key":"2025092202451741000_2025.09.16.676659v1.14","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab103"},{"key":"2025092202451741000_2025.09.16.676659v1.15","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa269"},{"key":"2025092202451741000_2025.09.16.676659v1.16","doi-asserted-by":"crossref","first-page":"4286","DOI":"10.1038\/s41467-023-39857-9","article-title":"Vgamma1 and Vgamma4 gamma- delta T cells play opposing roles in the immunopathology of traumatic brain injury in males","volume":"14","year":"2023","journal-title":"Nat Commun"},{"key":"2025092202451741000_2025.09.16.676659v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4633"},{"key":"2025092202451741000_2025.09.16.676659v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.09.046"},{"key":"2025092202451741000_2025.09.16.676659v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2011.12.003"},{"key":"2025092202451741000_2025.09.16.676659v1.20","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-3816-2_11"},{"key":"2025092202451741000_2025.09.16.676659v1.21","doi-asserted-by":"crossref","unstructured":"Romine J , Gao X , Chen J : Controlled cortical impact model for traumatic brain injury. J Vis Exp 2014:e51781.","DOI":"10.3791\/51781-v"},{"key":"2025092202451741000_2025.09.16.676659v1.22","doi-asserted-by":"crossref","unstructured":"Alder J , Fujioka W , Lifshitz J , Crockett DP , Thakker-Varia S: Lateral fluid percussion: model of traumatic brain injury in mice. J Vis Exp 2011.","DOI":"10.3791\/3063-v"},{"key":"2025092202451741000_2025.09.16.676659v1.23","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1067-18.2018"},{"key":"2025092202451741000_2025.09.16.676659v1.24","doi-asserted-by":"publisher","DOI":"10.31887\/DCNS.2011.13.2\/tmcallister"},{"key":"2025092202451741000_2025.09.16.676659v1.25","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4871-11.2011"},{"key":"2025092202451741000_2025.09.16.676659v1.26","unstructured":"!!! INVALID CITATION !!! [18]."},{"key":"2025092202451741000_2025.09.16.676659v1.27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0907143106"},{"key":"2025092202451741000_2025.09.16.676659v1.28","doi-asserted-by":"crossref","unstructured":"Itoh N , Ohta H : Roles of FGF20 in dopaminergic neurons and Parkinson\u2019s disease. Front Mol Neurosci 2013, 6:15.","DOI":"10.3389\/fnmol.2013.00015"},{"key":"2025092202451741000_2025.09.16.676659v1.29","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0614-15.2015"},{"key":"2025092202451741000_2025.09.16.676659v1.30","doi-asserted-by":"crossref","unstructured":"Sutter PA , Menoret A , Jellison ER , Nicaise AM , Bradbury AM , Vella AT , Bongarzone ER , Crocker SJ : CD8+ T cell depletion prevents neuropathology in a mouse model of globoid cell leukodystrophy. J Exp Med 2023, 220.","DOI":"10.1084\/jem.20221862"},{"key":"2025092202451741000_2025.09.16.676659v1.31","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.24830"},{"key":"2025092202451741000_2025.09.16.676659v1.32","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2010.1723"},{"key":"2025092202451741000_2025.09.16.676659v1.33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0908005106"},{"key":"2025092202451741000_2025.09.16.676659v1.34","doi-asserted-by":"crossref","unstructured":"Gomez-Benito M , Granado N , Garcia-Sanz P , Michel A , Dumoulin M , Moratalla R : Modeling Parkinson\u2019s Disease With the Alpha-Synuclein Protein. Front Pharmacol 2020, 11:356.","DOI":"10.3389\/fphar.2020.00356"},{"key":"2025092202451741000_2025.09.16.676659v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2016.09.003"},{"key":"2025092202451741000_2025.09.16.676659v1.36","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3233\/JPD-2011-11023","article-title":"MPTP mouse models of Parkinson\u2019s disease: an update","volume":"1","year":"2011","journal-title":"J Parkinsons Dis"},{"key":"2025092202451741000_2025.09.16.676659v1.37","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.2003.02781.x"},{"key":"2025092202451741000_2025.09.16.676659v1.38","doi-asserted-by":"publisher","DOI":"10.1002\/syn.20456"},{"key":"2025092202451741000_2025.09.16.676659v1.39","doi-asserted-by":"crossref","unstructured":"Sommer A , Fadler T , Dorfmeister E , Hoffmann AC , Xiang W , Winner B , Prots I : Infiltrating T lymphocytes reduce myeloid phagocytosis activity in synucleinopathy model. J Neuroinflammation 2016, 13:174.","DOI":"10.1186\/s12974-016-0632-5"},{"key":"2025092202451741000_2025.09.16.676659v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-024-01682-8"},{"key":"2025092202451741000_2025.09.16.676659v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/S41586-023-05788-0"},{"key":"2025092202451741000_2025.09.16.676659v1.42","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1002\/ana.27202","article-title":"Nigral Neuroinflammation and Dopaminergic Neurons in Parkinson\u2019s Disease and Atypical Parkinsonisms","volume":"97","year":"2025","journal-title":"Ann Neurol"},{"key":"2025092202451741000_2025.09.16.676659v1.43","doi-asserted-by":"crossref","unstructured":"Percie du Sert N , Hurst V , Ahluwalia A , Alam S , Avey MT , Baker M , Browne WJ , Clark A , Cuthill IC , Dirnagl U , et al: The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. BMC Vet Res 2020, 16:242.","DOI":"10.1186\/s12917-020-02451-y"},{"key":"2025092202451741000_2025.09.16.676659v1.44","doi-asserted-by":"publisher","DOI":"10.3233\/JPD-191683"},{"key":"2025092202451741000_2025.09.16.676659v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-444-52892-6.00001-5"},{"key":"2025092202451741000_2025.09.16.676659v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsr.2012.08.011"},{"key":"2025092202451741000_2025.09.16.676659v1.47","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07906-y"},{"key":"2025092202451741000_2025.09.16.676659v1.48","doi-asserted-by":"publisher","DOI":"10.1038\/nature22815"},{"key":"2025092202451741000_2025.09.16.676659v1.49","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.cobeha.2018.05.007","article-title":"Sex Differences in the Neuroimmune System","volume":"23","year":"2018","journal-title":"Curr Opin Behav Sci"},{"key":"2025092202451741000_2025.09.16.676659v1.50","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-9124-2_5"},{"key":"2025092202451741000_2025.09.16.676659v1.51","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20112457"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.09.16.676659","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T09:36:14Z","timestamp":1768469774000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.09.16.676659"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,17]]},"references-count":51,"URL":"https:\/\/doi.org\/10.1101\/2025.09.16.676659","relation":{},"subject":[],"published":{"date-parts":[[2025,9,17]]},"subtype":"preprint"}}