{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:10:43Z","timestamp":1791331843467,"version":"4.3.1"},"reference-count":144,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,12]],"date-time":"2025-04-12T00:00:00Z","timestamp":1744416000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH NINDS","award":["R01 NS113921"],"award-info":[{"award-number":["R01 NS113921"]}]},{"name":"NIH NINDS","award":["R01 NS107417"],"award-info":[{"award-number":["R01 NS107417"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Hypothermia (HT) is used clinically for neonatal hypoxic\u2013ischemic encephalopathy (HIE); however, the brain protection is incomplete and selective regional vulnerability and lifelong consequences remain. Refractory damage and impairment with HT cooling\/rewarming could result from unchecked or altered persisting cell death and proteinopathy. We tested two hypotheses: (1) HT modifies neurodegeneration type, and (2) intrinsically disordered proteins (IDPs) and encephalopathy cause toxic conformer protein (TCP) proteinopathy neonatally. We studied postmortem human neonatal HIE cases with or without therapeutic HT, neonatal piglets subjected to global hypoxia-ischemia (HI) with and without HT or combinations of HI and quinolinic acid (QA) excitotoxicity surviving for 29\u201396 h to 14 days, and human oligodendrocytes and neurons exposed to QA for cell models. In human and piglet encephalopathies with normothermia, the neuropathology by hematoxylin and eosin staining was similar; necrotic cell degeneration predominated. With HT, neurodegeneration morphology shifted to apoptosis-necrosis hybrid and apoptotic forms in human HIE, while neurons in HI piglets were unshifting and protected robustly. Oligomers and putative TCPs of \u03b1-synuclein (\u03b1Syn), nitrated-Syn and aggregated \u03b1Syn, misfolded\/oxidized superoxide dismutase-1 (SOD1), and prion protein (PrP) were detected with highly specific antibodies by immunohistochemistry, immunofluorescence, and immunoblotting. \u03b1Syn and SOD1 TCPs were seen in human HIE brains regardless of HT treatment. \u03b1Syn and SOD1 TCPs were detected as early as 29 h after injury in piglets and QA-injured human oligodendrocytes and neurons in culture. Cell immunophenotyping by immunofluorescence showed \u03b1Syn detected with antibodies to aggregated\/oligomerized protein; nitrated-Syn accumulated in neurons, sometimes appearing as focal dendritic aggregations. Co-localization also showed aberrant \u03b1Syn accumulating in presynaptic terminals. Proteinase K-resistant PrP accumulated in ischemic Purkinje cells, and their target regions had PrP-positive neuritic plaque-like pathology. Immunofluorescence revealed misfolded\/oxidized SOD1 in neurons, axons, astrocytes, and oligodendrocytes. HT attenuated TCP formation in piglets. We conclude that HT differentially affects brain damage in humans and piglets. HT shifts neuronal cell death to other forms in human while blocking ischemic necrosis in piglet for sustained protection. HI and excitotoxicity also acutely induce formation of TCPs and prion-like proteins from IDPs globally throughout the brain in gray matter and white matter. HT attenuates proteinopathy in piglets but seemingly not in humans. Shifting of cell death type and aberrant toxic protein formation could explain the selective system vulnerability, connectome spreading, and persistent damage seen in neonatal HIE leading to lifelong consequences even after HT treatment.<\/jats:p>","DOI":"10.3390\/cells14080586","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T09:06:51Z","timestamp":1744621611000},"page":"586","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Hypothermia Shifts Neurodegeneration Phenotype in Neonatal Human Hypoxic\u2013Ischemic Encephalopathy but Not in Related Piglet Models: Possible Relationship to Toxic Conformer and Intrinsically Disordered Prion-like Protein Accumulation"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8961-7020","authenticated-orcid":false,"given":"Lee J.","family":"Martin","sequence":"first","affiliation":[{"name":"Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA"},{"name":"Department of Neuroscience, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA"},{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA"},{"name":"The Pathobiology Graduate Training Program, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer K.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark V.","family":"Niedzwiecki","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Amrein Almira","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron","family":"Javdan","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2644-1667","authenticated-orcid":false,"given":"May W.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Johns Hopkins University School of Medicine, CMSC, 600 North Wolfe Street, Baltimore, MD 21287-0001, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Olberding","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1347-5908","authenticated-orcid":false,"given":"Stephen M.","family":"Brown","sequence":"additional","affiliation":[{"name":"The Pathobiology Graduate Training Program, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0065-7945","authenticated-orcid":false,"given":"Dongseok","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Yohannan","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasitha","family":"Putcha","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Becky","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalise","family":"Garrido","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan","family":"Benderoth","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chloe","family":"Kisner","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0122-4466","authenticated-orcid":false,"given":"Javid","family":"Ghaemmaghami","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC 20010-2916, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances J.","family":"Northington","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Johns Hopkins University School of Medicine, CMSC, 600 North Wolfe Street, Baltimore, MD 21287-0001, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7368-0436","authenticated-orcid":false,"given":"Panagiotis","family":"Kratimenos","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC 20010-2916, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.2471\/BLT.14.139790","article-title":"Neonatal cause-of-death estimates for the early and late neonatal periods for 194 countries: 2000\u20132013","volume":"93","author":"Oza","year":"2015","journal-title":"Bull. 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