[en] Finding novel biomarkers for Parkinson's disease (PD) is crucial for early disease diagnosis, severity assessment and identifying novel disease-modifying drug targets. Our study aimed at investigating the GATA3 mRNA levels in whole blood samples of idiopathic PD (iPD) patients with different disease severities as a biomarker for iPD. The present study is a cross-sectional, case-control study, with samples obtained from the Luxembourg Parkinson's cohort (LuxPARK). iPD (N = 319) patients, along with age-matched controls without PD (non-PD; N = 319) were included in this study. Blood GATA3 mRNA expression was measured using quantitative reverse transcription PCR (RT-qPCR) assays. The capacity of GATA3 expression levels to establish the diagnosis of iPD (primary end-point) and assess disease severity (secondary end-point) was determined. The blood levels of GATA3 were significantly lower in iPD patients, compared to non-PD controls (p ≤ 0.001). Logistic regression models showed a significant association of GATA3 expression with iPD diagnosis after adjustment for the confounders (p = 0.005). Moreover, the addition of GATA3 expression to a baseline clinical model improved its iPD diagnosis capacity (p = 0.005). There was a significant association of GATA3 expression levels with the overall disease severity (p = 0.002), non-motor experiences of daily living (nm-EDL; p = 0.003) and sleep disturbances (p = 0.01). Our results suggest that GATA3 expression measured in blood may serve as a novel biomarker and may help in the diagnosis of iPD and assessment of disease severity.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
ACHARYA, Shubhra ; University of Luxembourg ; Cardiovascular Research Unit, Department of Precision Health, Luxembourg Institute of Health, L-1445 Strassen, Luxembourg
Lumley, Andrew I ; Cardiovascular Research Unit, Department of Precision Health, Luxembourg Institute of Health, L-1445 Strassen, Luxembourg
Zhang, Lu ; Bioinformatics Platform, Luxembourg Institute of Health, L-1445 Strassen, Luxembourg
Vausort, Mélanie ; Cardiovascular Research Unit, Department of Precision Health, Luxembourg Institute of Health, L-1445 Strassen, Luxembourg
DEVAUX, Yvan ; University of Luxembourg ; Cardiovascular Research Unit, Department of Precision Health, Luxembourg Institute of Health, L-1445 Strassen, Luxembourg
On Behalf Of The Ncer-Pd Consortium
External co-authors :
no
Language :
English
Title :
GATA3 as a Blood-Based RNA Biomarker for Idiopathic Parkinson's Disease.
Publication date :
12 June 2023
Journal title :
International Journal of Molecular Sciences
ISSN :
1661-6596
eISSN :
1422-0067
Publisher :
Multidisciplinary Digital Publishing Institute (MDPI), Switzerland
Special issue title :
Peripheral Biomarkers in Neurodegenerative Diseases 3.0
FNR14566210 - Long Noncoding Rnas In Tissue Repair, 2020 (01/08/2020-31/07/2023) - Shubhra Acharya
Funders :
Fonds National de la Recherche Fonds National de la Recherche Fonds National de la Recherche Ministry of Higher Education and Research of Luxembourg, the Heart Foundation—Daniel Wagner Luxembourg National Research Fund
Funding text :
This work has been funded by grants from the Fonds National de la Recherche (FNR) of Luxembourg to S.A. (grant #AFR14566210) and to Y.D. (C14/BM/8225223, C17/BM/11613033) and the Ministry of Higher Education and Research of Luxembourg, the Heart Foundation—Daniel Wagner. The National Centre of Excellence in Research on Parkinson’s Disease (NCER-PD) is funded by the Luxembourg National Research Fund (FNR/NCER13/BM/11264123).
Michel P.P. Hirsch E.C. Hunot S. Understanding Dopaminergic Cell Death Pathways in Parkinson Disease Neuron 2016 90 675 691 10.1016/j.neuron.2016.03.038 27196972
Pellicano C. Benincasa D. Pisani V. Buttarelli F.R. Giovannelli M. Pontieri F.E. Prodromal non-motor symptoms of Parkinson’s disease Neuropsychiatr. Dis. Treat. 2007 3 145 152 10.2147/nedt.2007.3.1.145 19300544
Dorsey E.R. Constantinescu R. Thompson J.P. Biglan K.M. Holloway R.G. Kieburtz K. Marshall F.J. Ravina B.M. Schifitto G. Siderowf A. et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030 Neurology 2007 68 384 386 10.1212/01.wnl.0000247740.47667.03 17082464
Comi C. Cosentino M. Pacheco R. Editorial: Peripheral Immunity in Parkinson’s Disease: Emerging Role and Novel Target for Therapeutics Front. Neurol. 2019 10 1080 10.3389/fneur.2019.01080
Chen L. Mo M. Li G. Cen L. Wei L. Xiao Y. Chen X. Li S. Yang X. Qu S. et al. The biomarkers of immune dysregulation and inflammation response in Parkinson disease Transl. Neurodegener. 2016 5 16 10.1186/s40035-016-0063-3
Brochard V. Combadiere B. Prigent A. Laouar Y. Perrin A. Beray-Berthat V. Bonduelle O. Alvarez-Fischer D. Callebert J. Launay J.M. et al. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease J. Clin. Investig. 2009 119 182 192 10.1172/JCI36470
Williams G.P. Schonhoff A.M. Jurkuvenaite A. Gallups N.J. Standaert D.G. Harms A.S. CD4 T cells mediate brain inflammation and neurodegeneration in a mouse model of Parkinson’s disease Brain 2021 144 2047 2059 10.1093/brain/awab103
Karikari A.A. McFleder R.L. Ribechini E. Blum R. Bruttel V. Knorr S. Gehmeyr M. Volkmann J. Brotchie J.M. Ahsan F. et al. Neurodegeneration by alpha-synuclein-specific T cells in AAV-A53T-alpha-synuclein Parkinson’s disease mice Brain Behav. Immun. 2022 101 194 210 10.1016/j.bbi.2022.01.007
Bhatia D. Grozdanov V. Ruf W.P. Kassubek J. Ludolph A.C. Weishaupt J.H. Danzer K.M. T-cell dysregulation is associated with disease severity in Parkinson’s Disease J. Neuroinflamm. 2021 18 250 10.1186/s12974-021-02296-8
Contaldi E. Magistrelli L. Milner A.V. Cosentino M. Marino F. Comi C. Expression of Transcription Factors in CD4 + T Cells as Potential Biomarkers of Motor Complications in Parkinson’s Disease J. Parkinson’s Dis. 2021 11 507 514 10.3233/JPD-202417
De Francesco E. Terzaghi M. Storelli E. Magistrelli L. Comi C. Legnaro M. Mauri M. Marino F. Versino M. Cosentino M. CD4+ T-cell Transcription Factors in Idiopathic REM Sleep Behavior Disorder and Parkinson’s Disease Mov. Disord. 2021 36 225 229 10.1002/mds.28137
Ho I.C. Tai T.S. Pai S.Y. GATA3 and the T-cell lineage: Essential functions before and after T-helper-2-cell differentiation Nat. Rev. Immunol. 2009 9 125 135 10.1038/nri2476
Zhao G.Y. Li Z.Y. Zou H.L. Hu Z.L. Song N.N. Zheng M.H. Su C.J. Ding Y.Q. Expression of the transcription factor GATA3 in the postnatal mouse central nervous system Neurosci. Res. 2008 61 420 428 10.1016/j.neures.2008.04.014
Zagare A. Barmpa K. Smajic S. Smits L.M. Grzyb K. Grunewald A. Skupin A. Nickels S.L. Schwamborn J.C. Midbrain organoids mimic early embryonic neurodevelopment and recapitulate LRRK2-p.Gly2019Ser-associated gene expression Am. J. Hum. Genet. 2022 109 311 327 10.1016/j.ajhg.2021.12.009
Hong S.J. Huh Y. Chae H. Hong S. Lardaro T. Kim K.S. GATA-3 regulates the transcriptional activity of tyrosine hydroxylase by interacting with CREB J. Neurochem. 2006 98 773 781 10.1111/j.1471-4159.2006.03924.x
Daubner S.C. Le T. Wang S. Tyrosine hydroxylase and regulation of dopamine synthesis Arch. Biochem. Biophys. 2011 508 1 12 10.1016/j.abb.2010.12.017
Tsarovina K. Reiff T. Stubbusch J. Kurek D. Grosveld F.G. Parlato R. Schutz G. Rohrer H. The Gata3 transcription factor is required for the survival of embryonic and adult sympathetic neurons J. Neurosci. 2010 30 10833 10843 10.1523/JNEUROSCI.0175-10.2010
Wan Y.Y. GATA3: A master of many trades in immune regulation Trends Immunol. 2014 35 233 242 10.1016/j.it.2014.04.002
Fayyad M. Salim S. Majbour N. Erskine D. Stoops E. Mollenhauer B. El-Agnaf O.M.A. Parkinson’s disease biomarkers based on alpha-synuclein J. Neurochem. 2019 150 626 636 10.1111/jnc.14809
Acharya S. Lumley A.I. Devaux Y. Targeting regulatory RNAs at the heart of Parkinson’s disease Eur. Heart J. 2023 ehad010 10.1093/eurheartj/ehad010
Acharya S. Salgado-Somoza A. Stefanizzi F.M. Lumley A.I. Zhang L. Glaab E. May P. Devaux Y. Non-Coding RNAs in the Brain-Heart Axis: The Case of Parkinson’s Disease Int. J. Mol. Sci. 2020 21 6513 10.3390/ijms21186513 32899928
Hipp G. Vaillant M. Diederich N.J. Roomp K. Satagopam V.P. Banda P. Sandt E. Mommaerts K. Schmitz S.K. Longhino L. et al. The Luxembourg Parkinson’s Study: A Comprehensive Approach for Stratification and Early Diagnosis Front. Aging Neurosci. 2018 10 326 10.3389/fnagi.2018.00326 30420802
Haaxma C.A. Bloem B.R. Borm G.F. Oyen W.J. Leenders K.L. Eshuis S. Booij J. Dluzen D.E. Horstink M.W. Gender differences in Parkinson’s disease J. Neurol. Neurosurg. Psychiatry 2007 78 819 824 10.1136/jnnp.2006.103788 17098842
Wooten G.F. Currie L.J. Bovbjerg V.E. Lee J.K. Patrie J. Are men at greater risk for Parkinson’s disease than women? J. Neurol. Neurosurg. Psychiatry 2004 75 637 639 10.1136/jnnp.2003.020982 15026515
Khazaeli Najafabadi M. Mirzaeian E. Memar Montazerin S. Tavangar A.R. Tabary M. Tavangar S.M. Role of GATA3 in tumor diagnosis: A review Pathol. Res. Pract. 2021 226 153611 10.1016/j.prp.2021.153611
Ai D. Yao J. Yang F. Huo L. Chen H. Lu W. Soto L.M.S. Jiang M. Raso M.G. Wang S. et al. TRPS1: A highly sensitive and specific marker for breast carcinoma, especially for triple-negative breast cancer Mod. Pathol. 2021 34 710 719 10.1038/s41379-020-00692-8
Kustrimovic N. Rasini E. Legnaro M. Bombelli R. Aleksic I. Blandini F. Comi C. Mauri M. Minafra B. Riboldazzi G. et al. Dopaminergic Receptors on CD4+ T Naive and Memory Lymphocytes Correlate with Motor Impairment in Patients with Parkinson’s Disease Sci. Rep. 2016 6 33738 10.1038/srep33738
Kustrimovic N. Comi C. Magistrelli L. Rasini E. Legnaro M. Bombelli R. Aleksic I. Blandini F. Minafra B. Riboldazzi G. et al. Parkinson’s disease patients have a complex phenotypic and functional Th1 bias: Cross-sectional studies of CD4+ Th1/Th2/T17 and Treg in drug-naive and drug-treated patients J. Neuroinflamm. 2018 15 205 10.1186/s12974-018-1248-8
Devaux Y. Transcriptome of blood cells as a reservoir of cardiovascular biomarkers Biochim. Biophys. Acta Mol. Cell Res. 2017 1864 209 216 10.1016/j.bbamcr.2016.11.005
Vanhaverbeke M. Attard R. Bartekova M. Ben-Aicha S. Brandenburger T. de Gonzalo-Calvo D. Emanueli C. Farrugia R. Grillari J. Hackl M. et al. Peripheral blood RNA biomarkers for cardiovascular disease from bench to bedside: A position paper from the EU-CardioRNA COST action CA17129 Cardiovasc. Res. 2022 118 3183 3197 10.1093/cvr/cvab327
Lalem T. Zhang L. Scholz M. Burkhardt R. Saccheti V. Teren A. Thiery J. Devaux Y. Cardiolinc n. Cyclin dependent kinase inhibitor 1 C is a female-specific marker of left ventricular function after acute myocardial infarction Int. J. Cardiol. 2019 274 319 325 10.1016/j.ijcard.2018.07.042
Mattsson-Carlgren N. Salvado G. Ashton N.J. Tideman P. Stomrud E. Zetterberg H. Ossenkoppele R. Betthauser T.J. Cody K.A. Jonaitis E.M. et al. Prediction of Longitudinal Cognitive Decline in Preclinical Alzheimer Disease Using Plasma Biomarkers JAMA Neurol. 2023 80 360 369 10.1001/jamaneurol.2022.5272
Marek K. Chowdhury S. Siderowf A. Lasch S. Coffey C.S. Caspell-Garcia C. Simuni T. Jennings D. Tanner C.M. Trojanowski J.Q. et al. The Parkinson’s progression markers initiative (PPMI)—Establishing a PD biomarker cohort Ann. Clin. Transl. Neurol. 2018 5 1460 1477 10.1002/acn3.644
Lang A.E. Eberly S. Goetz C.G. Stebbins G. Oakes D. Marek K. Ravina B. Tanner C.M. Shoulson I. LABS-PD investigators Movement disorder society unified Parkinson disease rating scale experiences in daily living: Longitudinal changes and correlation with other assessments Mov. Disord. 2013 28 1980 1986 10.1002/mds.25671
Abbott R.D. Ross G.W. White L.R. Tanner C.M. Masaki K.H. Nelson J.S. Curb J.D. Petrovitch H. Excessive daytime sleepiness and subsequent development of Parkinson disease Neurology 2005 65 1442 1446 10.1212/01.wnl.0000183056.89590.0d
Gao J. Huang X. Park Y. Hollenbeck A. Blair A. Schatzkin A. Chen H. Daytime napping, nighttime sleeping, and Parkinson disease Am. J. Epidemiol. 2011 173 1032 1038 10.1093/aje/kwq478
Siderowf A. Concha-Marambio L. Lafontant D.E. Farris C.M. Ma Y. Urenia P.A. Nguyen H. Alcalay R.N. Chahine L.M. Foroud T. et al. Assessment of heterogeneity among participants in the Parkinson’s Progression Markers Initiative cohort using alpha-synuclein seed amplification: A cross-sectional study Lancet Neurol. 2023 22 407 417 10.1016/S1474-4422(23)00109-6
Okuzumi A. Hatano T. Matsumoto G. Nojiri S. Ueno S.I. Imamichi-Tatano Y. Kimura H. Kakuta S. Kondo A. Fukuhara T. et al. Propagative alpha-synuclein seeds as serum biomarkers for synucleinopathies Nat. Med. 2023 10.1038/s41591-023-02358-9
Clarke C.E. Patel S. Ives N. Rick C.E. Woolley R. Wheatley K. PD REHAB Collaborative Group Clinical effectiveness and cost-effectiveness of physiotherapy and occupational therapy versus no therapy in mild to moderate Parkinson’s disease: A large pragmatic randomised controlled trial (PD REHAB) NIHR J. Libr. 2016 20 1 96 10.3310/hta20630
Lehmann S. Guadagni F. Moore H. Ashton G. Barnes M. Benson E. Clements J. Koppandi I. Coppola D. Demiroglu S.Y. et al. Standard preanalytical coding for biospecimens: Review and implementation of the Sample PREanalytical Code (SPREC) Biopreserv. Biobank. 2012 10 366 374 10.1089/bio.2012.0012