{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:55:28Z","timestamp":1791222928295,"version":"4.1.0"},"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003554","name":"Lundbeck Foundation","doi-asserted-by":"publisher","award":["R361-2020-2654"],"award-info":[{"award-number":["R361-2020-2654"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosbiology.org"],"crossmark-restriction":false},"short-container-title":["PLoS Biol"],"abstract":"<jats:p>Neurodegenerative diseases often damage some neuronal populations while sparing closely related neighbors. But instead of asking why some neurons die, should we be asking why some survive? This Essay proposes that a neuron\u2019s capacity to sustain the gene-regulatory machinery that maintains its subtype identity helps set the stress threshold beyond which recovery fails. The initiating insult may be metabolic, proteostatic, inflammatory, or arise from the surrounding tissue, but it is the cell\u2019s capacity for maintenance that will determine where the tipping point lies: above a critical level, the identity program recovers, whereas below it, regulatory loss becomes self-sustaining. Such a framing could have implications for how neuronal vulnerability to neurodegeneration is understood.<\/jats:p>","DOI":"10.1371\/journal.pbio.3004014","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:21:21Z","timestamp":1791220881000},"page":"e3004014","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Why are some neurons spared in neurodegeneration? Cellular subtype identity maintenance as a candidate threshold-setting mechanism"],"prefix":"10.1371","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8624-0168","authenticated-orcid":true,"given":"Dong Won","family":"Kim","sequence":"first","affiliation":[{"name":"Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Aarhus University","place":["Aarhus, Denmark"]},{"name":"Aarhus University","place":["Aarhus, Denmark"],"department":["Department of Biomedicine"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"issue":"2","key":"pbio.3004014.ref001","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nrn.2016.178","article-title":"Selective neuronal vulnerability in Parkinson disease","volume":"18","author":"DJ Surmeier","year":"2017","journal-title":"Nat Rev Neurosci"},{"issue":"10","key":"pbio.3004014.ref002","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1038\/s41593-018-0221-2","article-title":"Selective vulnerability in neurodegenerative diseases","volume":"21","author":"H Fu","year":"2018","journal-title":"Nat Neurosci"},{"key":"pbio.3004014.ref003","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.baga.2015.06.001","article-title":"The vulnerable ventral tegmental area in Parkinson\u2019s disease","volume":"5","author":"SL Alberico","year":"2015","journal-title":"Basal Ganglia"},{"issue":"14","key":"pbio.3004014.ref004","doi-asserted-by":"crossref","first-page":"4491","DOI":"10.1523\/JNEUROSCI.16-14-04491.1996","article-title":"Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer\u2019s disease","volume":"16","author":"T G\u00f3mez-Isla","year":"1996","journal-title":"J Neurosci"},{"issue":"6","key":"pbio.3004014.ref005","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1007\/s00401-017-1708-8","article-title":"Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis","volume":"133","author":"J Nijssen","year":"2017","journal-title":"Acta Neuropathol"},{"issue":"5","key":"pbio.3004014.ref006","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nn.2297","article-title":"A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice","volume":"12","author":"S Saxena","year":"2009","journal-title":"Nat Neurosci"},{"issue":"1","key":"pbio.3004014.ref007","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.neuron.2011.06.031","article-title":"Selective neuronal vulnerability in neurodegenerative diseases: from stressor thresholds to degeneration","volume":"71","author":"S Saxena","year":"2011","journal-title":"Neuron"},{"issue":"7","key":"pbio.3004014.ref008","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1038\/nn.3731","article-title":"Maintenance of postmitotic neuronal cell identity","volume":"17","author":"ES Deneris","year":"2014","journal-title":"Nat Neurosci"},{"issue":"4","key":"pbio.3004014.ref009","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1002\/wdev.233","article-title":"A map of terminal regulators of neuronal identity in Caenorhabditis elegans","volume":"5","author":"O Hobert","year":"2016","journal-title":"Wiley Interdiscip Rev Dev Biol"},{"key":"pbio.3004014.ref010","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.conb.2018.12.006","article-title":"Neuronal identity control by terminal selectors in worms, flies, and chordates","volume":"56","author":"O Hobert","year":"2019","journal-title":"Curr Opin Neurobiol"},{"key":"pbio.3004014.ref011","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.50065","article-title":"A terminal selector prevents a Hox transcriptional switch to safeguard motor neuron identity throughout life","volume":"9","author":"W Feng","year":"2020","journal-title":"Elife"},{"issue":"10","key":"pbio.3004014.ref012","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1038\/nn.2623","article-title":"Pet-1 is required across different stages of life to regulate serotonergic function","volume":"13","author":"C Liu","year":"2010","journal-title":"Nat Neurosci"},{"issue":"49","key":"pbio.3004014.ref013","doi-asserted-by":"crossref","first-page":"12781","DOI":"10.1523\/JNEUROSCI.4143-06.2006","article-title":"Lmx1b is required for maintenance of central serotonergic neurons and mice lacking central serotonergic system exhibit normal locomotor activity","volume":"26","author":"Z-Q Zhao","year":"2006","journal-title":"J Neurosci"},{"issue":"12","key":"pbio.3004014.ref014","doi-asserted-by":"crossref","first-page":"109269","DOI":"10.1016\/j.celrep.2021.109269","article-title":"Transcriptional repression by FEZF2 restricts alternative identities of cortical projection neurons","volume":"35","author":"J Tsyporin","year":"2021","journal-title":"Cell Rep"},{"key":"pbio.3004014.ref015","article-title":"Establishment and maintenance of motor neuron identity via temporal modularity in terminal selector function","volume":"9","author":"Y Li","year":"2020","journal-title":"Elife"},{"key":"pbio.3004014.ref016","article-title":"Transgenic reporter analysis of ChIP-Seq-defined enhancers identifies novel target genes for the terminal selector UNC-3\/Collier\/Ebf","volume":"2021","author":"Y Li","year":"2021","journal-title":"MicroPubl Biol"},{"issue":"34","key":"pbio.3004014.ref017","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.abo1543","article-title":"PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons","volume":"8","author":"K Toskas","year":"2022","journal-title":"Sci Adv"},{"issue":"10","key":"pbio.3004014.ref018","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1038\/nn.4360","article-title":"Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration","volume":"19","author":"M von Schimmelmann","year":"2016","journal-title":"Nat Neurosci"},{"issue":"7","key":"pbio.3004014.ref019","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1093\/emboj\/21.7.1505","article-title":"An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype","volume":"21","author":"JT Wigle","year":"2002","journal-title":"EMBO J"},{"issue":"23","key":"pbio.3004014.ref020","doi-asserted-by":"crossref","first-page":"3282","DOI":"10.1101\/gad.1727208","article-title":"Lymphatic endothelial cell identity is reversible and its maintenance requires Prox1 activity","volume":"22","author":"NC Johnson","year":"2008","journal-title":"Genes Dev"},{"issue":"7358","key":"pbio.3004014.ref021","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nature10239","article-title":"DMRT1 prevents female reprogramming in the postnatal mammalian testis","volume":"476","author":"CK Matson","year":"2011","journal-title":"Nature"},{"issue":"50","key":"pbio.3004014.ref022","doi-asserted-by":"crossref","first-page":"15923","DOI":"10.1523\/JNEUROSCI.3910-09.2009","article-title":"Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons","volume":"29","author":"B Kadkhodaei","year":"2009","journal-title":"J Neurosci"},{"issue":"6","key":"pbio.3004014.ref023","doi-asserted-by":"crossref","first-page":"2360","DOI":"10.1073\/pnas.1221077110","article-title":"Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons","volume":"110","author":"B Kadkhodaei","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"163","key":"pbio.3004014.ref024","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.3004676","article-title":"\u03b1-Synuclein-induced down-regulation of Nurr1 disrupts GDNF signaling in nigral dopamine neurons","volume":"4","author":"M Decressac","year":"2012","journal-title":"Sci Transl Med"},{"issue":"1","key":"pbio.3004014.ref025","doi-asserted-by":"crossref","first-page":"4283","DOI":"10.1038\/s41467-023-39970-9","article-title":"An optimized Nurr1 agonist provides disease-modifying effects in Parkinson\u2019s disease models","volume":"14","author":"W Kim","year":"2023","journal-title":"Nat Commun"},{"issue":"2","key":"pbio.3004014.ref026","doi-asserted-by":"crossref","first-page":"171","DOI":"10.15252\/emmm.201506162","article-title":"Combined Nurr1 and Foxa2 roles in the therapy of Parkinson\u2019s disease","volume":"8","author":"S-M Oh","year":"2016","journal-title":"EMBO Mol Med"},{"issue":"27","key":"pbio.3004014.ref027","doi-asserted-by":"crossref","first-page":"12317","DOI":"10.1073\/pnas.1007088107","article-title":"NR4A orphan nuclear receptors as mediators of CREB-dependent neuroprotection","volume":"107","author":"N Volakakis","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"pbio.3004014.ref028","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1242\/dev.029769","article-title":"Pitx3 potentiates Nurr1 in dopamine neuron terminal differentiation through release of SMRT-mediated repression","volume":"136","author":"FMJ Jacobs","year":"2009","journal-title":"Development"},{"issue":"7","key":"pbio.3004014.ref029","doi-asserted-by":"crossref","first-page":"4245","DOI":"10.1073\/pnas.0230529100","article-title":"Pitx3 is required for development of substantia nigra dopaminergic neurons","volume":"100","author":"I Nunes","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"11","key":"pbio.3004014.ref030","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.1242\/dev.00464","article-title":"Pitx3 is required for motor activity and for survival of a subset of midbrain dopaminergic neurons","volume":"130","author":"P van den Munckhof","year":"2003","journal-title":"Development"},{"issue":"11","key":"pbio.3004014.ref031","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1038\/s41419-021-04319-x","article-title":"The essential role of transcription factor Pitx3 in preventing mesodiencephalic dopaminergic neurodegeneration and maintaining neuronal subtype identities during aging","volume":"12","author":"Y Wang","year":"2021","journal-title":"Cell Death Dis"},{"key":"pbio.3004014.ref032","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.89482","article-title":"Transcriptomic atlas of midbrain dopamine neurons uncovers differential vulnerability in a Parkinsonism lesion model","volume":"12","author":"B Yaghmaeian Salmani","year":"2024","journal-title":"Elife"},{"issue":"11","key":"pbio.3004014.ref033","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1038\/s41422-022-00719-6","article-title":"Single-cell epigenome analysis reveals age-associated decay of heterochromatin domains in excitatory neurons in the mouse brain","volume":"32","author":"Y Zhang","year":"2022","journal-title":"Cell Res"},{"issue":"6","key":"pbio.3004014.ref034","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1038\/s41582-023-00809-y","article-title":"Single-cell and spatial transcriptomics: deciphering brain complexity in health and disease","volume":"19","author":"M Piwecka","year":"2023","journal-title":"Nat Rev Neurol"},{"key":"pbio.3004014.ref035","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1146\/annurev-immunol-051116-052358","article-title":"Microglia function in the central nervous system during health and neurodegeneration","volume":"35","author":"M Colonna","year":"2017","journal-title":"Annu Rev Immunol"},{"key":"pbio.3004014.ref036","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1016\/j.cell.2018.05.003","article-title":"Disease-associated microglia: a universal immune sensor of neurodegeneration","volume":"173","author":"A Deczkowska","year":"2018","journal-title":"Cell"},{"issue":"2","key":"pbio.3004014.ref037","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.cell.2022.11.001","article-title":"Hallmarks of aging: an expanding universe","volume":"186","author":"C L\u00f3pez-Ot\u00edn","year":"2023","journal-title":"Cell"},{"issue":"4","key":"pbio.3004014.ref038","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.cell.2022.12.032","article-title":"Hallmarks of neurodegenerative diseases","volume":"186","author":"MR Cookson","year":"2023","journal-title":"Cell"},{"issue":"7761","key":"pbio.3004014.ref039","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/s41586-019-1195-2","article-title":"Single-cell transcriptomic analysis of Alzheimer\u2019s disease","volume":"570","author":"H Mathys","year":"2019","journal-title":"Nature"},{"issue":"2","key":"pbio.3004014.ref040","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/s41593-020-00764-7","article-title":"Molecular characterization of selectively vulnerable neurons in Alzheimer\u2019s disease","volume":"24","author":"K Leng","year":"2021","journal-title":"Nat Neurosci"},{"issue":"20","key":"pbio.3004014.ref041","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2023.08.039","article-title":"Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer\u2019s disease pathology","volume":"186","author":"H Mathys","year":"2023","journal-title":"Cell"},{"issue":"10","key":"pbio.3004014.ref042","doi-asserted-by":"crossref","first-page":"2044","DOI":"10.1038\/s41593-025-02033-x","article-title":"Embryonic motor neuron programming factors reactivate immature gene expression and suppress ALS pathologies in postnatal motor neurons","volume":"28","author":"ER Lowry","year":"2025","journal-title":"Nat Neurosci"}],"container-title":["PLOS Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3004014","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:21:27Z","timestamp":1791220887000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3004014"}},"subtitle":[],"editor":[{"given":"Sarah","family":"J\u00e4kel","sequence":"first","affiliation":[{"name":"School of Medicine and Health, Technical University, Munich","place":["GERMANY"]}],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,10,5]]},"references-count":42,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,10,5]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pbio.3004014","relation":{},"ISSN":["1545-7885"],"issn-type":[{"value":"1545-7885","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,5]]}}}