{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T12:48:36Z","timestamp":1768308516900,"version":"3.49.0"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"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. Mol. Neurosci."],"abstract":"<jats:p>\n                    Parkinson\u2019s disease (PD) symptom onset is typically unilateral, which may be related to molecular differences underlying hemispheric vulnerability. Here we sampled prefrontal cortex bilaterally from people with PD and healthy controls and performed RNA-seq on neuronal nuclei to determine hemispheric and disease-related differences. Brain hemispheres were categorized based on whether they corresponded to the side of symptom onset (severe) or the opposite side (moderate) and compared for differences in gene expression. We employed two\n                    <jats:italic>a priori<\/jats:italic>\n                    approaches; first we identified genes differentially expressed between PD and controls and between PD brain hemispheres. Second, we examined the presence of, and correlates to, variations in the asymmetry for some differentially expressed genes. We found large variation among individuals with PD, and so PD stratification by gene expression signature was required for patterns of genetic asymmetry to emerge. For a subset of PD brains, hemispherical variation of\n                    <jats:italic>CCT<\/jats:italic>\n                    gene levels correlated with the side of PD symptom onset. In a mouse model of PD, neurons with\n                    <jats:italic>\u03b1<\/jats:italic>\n                    -synuclein inclusions had decreased\n                    <jats:italic>Cct<\/jats:italic>\n                    expression. These results suggest that\n                    <jats:italic>CCT<\/jats:italic>\n                    expression plays a protective role in PD.\n                  <\/jats:p>","DOI":"10.3389\/fnmol.2025.1743557","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T06:33:24Z","timestamp":1768286004000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Gene expression asymmetry in Parkinson\u2019s disease: variation of CCT gene expression is correlated with hemisphere specific severity"],"prefix":"10.3389","volume":"18","author":[{"given":"Steven E.","family":"Pierce","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edwin J. C.","family":"van der Schans","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas M.","family":"Goralski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Ensink","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peipei","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael X.","family":"Henderson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerhard A.","family":"Coetzee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"911942","DOI":"10.3389\/fonc.2022.911942","article-title":"Comprehensive analysis of the brain-expressed X-link protein family in glioblastoma Multiforme","volume":"12","author":"Aisa","year":"2022","journal-title":"Front. Oncol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.gene.2005.05.012","article-title":"Characterization of the Bex gene family in humans, mice, and rats","volume":"357","author":"Alvarez","year":"2005","journal-title":"Gene"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1136\/jnnp.2010.209783","article-title":"Handedness and motor symptom asymmetry in Parkinson's disease","volume":"82","author":"Barrett","year":"2011","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/s0197-4580(02)00065-9","article-title":"Staging of brain pathology related to sporadic Parkinson's disease","volume":"24","author":"Braak","year":"2003","journal-title":"Neurobiol. Aging"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1002\/mds.22896","article-title":"Motor laterality asymmetry and nonmotor symptoms in Parkinson's disease","volume":"25","author":"Cubo","year":"2010","journal-title":"Mov. Disord."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1016\/S1474-4422(06)70549-X","article-title":"The mystery of motor asymmetry in Parkinson's disease","volume":"5","author":"Djaldetti","year":"2006","journal-title":"Lancet Neurol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1007\/978-1-4939-3572-7_13","article-title":"Optimizing RNA-Seq mapping with STAR","volume":"1415","author":"Dobin","year":"2016","journal-title":"Methods Mol. Biol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1097\/00006231-200505000-00005","article-title":"123I-FP-CIT semi-quantitative SPECT detects preclinical bilateral dopaminergic deficit in early Parkinson's disease with unilateral symptoms","volume":"26","author":"Filippi","year":"2005","journal-title":"Nucl. Med. Commun."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1002\/ana.25441","article-title":"Concordance for Parkinson's disease in twins: a 20-year update","volume":"85","author":"Goldman","year":"2019","journal-title":"Ann. Neurol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"2642","DOI":"10.1038\/s41467-024-47027-8","article-title":"Spatial transcriptomics reveals molecular dysfunction associated with cortical Lewy pathology","volume":"15","author":"Goralski","year":"2024","journal-title":"Nat. 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Chem."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1126\/science.adp8721","article-title":"Brain malformations and seizures by impaired chaperonin function of TRiC","volume":"386","author":"Kraft","year":"2024","journal-title":"Science"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"6031","DOI":"10.1038\/s41598-017-04426-w","article-title":"A comparative strategy for single-nucleus and single-cell transcriptomes confirms accuracy in predicted cell-type expression from nuclear RNA","volume":"7","author":"Lake","year":"2017","journal-title":"Sci. Rep."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"668871","DOI":"10.3389\/fgene.2021.668871","article-title":"Prognostic power of a chaperonin containing TCP-1 subunit genes panel for hepatocellular carcinoma","volume":"12","author":"Li","year":"2021","journal-title":"Front. 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Biol."},{"key":"ref20","doi-asserted-by":"publisher","DOI":"10.3791\/914","article-title":"Neuronal nuclei isolation from human postmortem brain tissue","volume":"20","author":"Matevossian","year":"2008","journal-title":"J. Vis. Exp."},{"key":"ref21","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24020927","article-title":"Contribution of extracellular vesicles and molecular chaperones in age-related neurodegenerative disorders of the CNS","volume":"24","author":"Noori","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1038\/nbt.2931","article-title":"Normalization of RNA-seq data using factor analysis of control genes or samples","volume":"32","author":"Risso","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"ref6001","doi-asserted-by":"publisher","first-page":"R25","DOI":"10.1186\/gb-2010-11-3-r25","article-title":"A scaling normalization method for differential expression analysis of RNA-seq data","volume":"11","author":"Robinson","year":"2010","journal-title":"Genome Biol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"177","DOI":"10.4103\/0970-0218.183593","article-title":"Twin studies: a unique epidemiological tool","volume":"41","author":"Sahu","year":"2016","journal-title":"Indian J. Community Med."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"2180","DOI":"10.1038\/s41467-021-22369-9","article-title":"The landscape of molecular chaperones across human tissues reveals a layered architecture of core and variable chaperones","volume":"12","author":"Shemesh","year":"2021","journal-title":"Nat. Commun."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1080\/23279095.2021.1907392","article-title":"Laterality in Parkinson's disease: a neuropsychological review","volume":"30","author":"Steinbach","year":"2023","journal-title":"Appl. Neuropsychol. Adult"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref27","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines10123241","article-title":"Synucleins: new data on Misfolding, aggregation and role in diseases","volume":"10","author":"Surguchov","year":"2022","journal-title":"Biomedicine"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest","volume":"51","author":"Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1002\/mds.24007","article-title":"Handedness correlates with the dominant Parkinson side: a systematic review and meta-analysis","volume":"27","author":"van der Hoorn","year":"2012","journal-title":"Mov. Disord."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"100350","DOI":"10.1016\/j.prdoa.2025.100350","article-title":"Motor asymmetry in Parkinson's disease: diagnostic thresholds based on clinical scores and DaTSCAN imaging","volume":"12","author":"Voruz","year":"2025","journal-title":"Clin. Park. Relat. Disord."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1016\/j.jhep.2021.06.025","article-title":"DNMT1-mediated methylation of BEX1 regulates stemness and tumorigenicity in liver cancer","volume":"75","author":"Wang","year":"2021","journal-title":"J. Hepatol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.neulet.2013.03.057","article-title":"Increased SUMO-1 expression in the unilateral rotenone-lesioned mouse model of Parkinson\u2019s disease","volume":"544","author":"Weetman","year":"2013","journal-title":"Neurosci. Lett."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1136\/jnnp.2003.020982","article-title":"Are men at greater risk for Parkinson's disease than women?","volume":"75","author":"Wooten","year":"2004","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"4465","DOI":"10.1002\/hbm.25558","article-title":"Characterizing white matter alterations subject to clinical laterality in drug-naive de novo Parkinson's disease","volume":"42","author":"Xiao","year":"2021","journal-title":"Hum. Brain Mapp."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/j.currproblcancer.2017.02.007","article-title":"Effectiveness between early and late temporary ileostomy closure in patients with rectal cancer: a prospective study","volume":"41","author":"Zhen","year":"2017","journal-title":"Curr. Probl. 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