title: Nurr1:RXRα heterodimer activation as monotherapy for Parkinson's disease.
abstract: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra and the gradual depletion of dopamine (DA). Current treatments replenish the DA deficit and improve symptoms but induce dyskinesias over time, and neuroprotective therapies are nonexistent. Here we report that Nuclear receptor-related 1 (Nurr1):Retinoid X receptor α (RXRα) activation has a double therapeutic potential for PD, offering both neuroprotective and symptomatic improvement. We designed BRF110, a unique in vivo active Nurr1:RXRα-selective lead molecule, which prevents DAergic neuron demise and striatal DAergic denervation in vivo against PD-causing toxins in a Nurr1-dependent manner. BRF110 also protects against PD-related genetic mutations in patient induced pluripotent stem cell (iPSC)-derived DAergic neurons and a genetic mouse PD model. Remarkably, besides neuroprotection, BRF110 up-regulates tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase (AADC), and GTP cyclohydrolase I (GCH1) transcription; increases striatal DA in vivo; and has symptomatic efficacy in two postneurodegeneration PD models, without inducing dyskinesias on chronic daily treatment. The combined neuroprotective and symptomatic effects of BRF110 identify Nurr1:RXRα activation as a potential monotherapeutic approach for PD.
authors.affiliation: Center for Clinical Research, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece; dvassilatis@bioacademy.gr thansp@hotmail.com.
authors.forename: Athanasios D
authors.initials: AD
authors.lastname: Spathis
authors.affiliation: Department of Materials Science and Engineering, University of Ioannina, Ioannina 45110, Greece.
authors.forename: Xenophon
authors.initials: X
authors.lastname: Asvos
authors.affiliation: Center for Clinical Research, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece.
authors.forename: Despina
authors.initials: D
authors.lastname: Ziavra
authors.affiliation: Center for Clinical Research, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Karampelas
authors.affiliation: Department of Pharmacy, University of Patras, Patras 26504, Greece.
authors.forename: Stavros
authors.initials: S
authors.lastname: Topouzis
authors.affiliation: Center for Clinical Research, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Cournia
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette L-4367, Luxembourg.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Qing
authors.affiliation: Center for Clinical Research, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece.
authors.forename: Pavlos
authors.initials: P
authors.lastname: Alexakos
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette L-4367, Luxembourg.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Smits
authors.affiliation: Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Dalla
authors.affiliation: Center for Clinical Research, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece.
authors.forename: Hardy J
authors.initials: HJ
authors.lastname: Rideout
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette L-4367, Luxembourg.
authors.forename: Jens Christian
authors.initials: JC
authors.lastname: Schwamborn
authors.affiliation: Center for Clinical Research, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece.
authors.forename: Constantin
authors.initials: C
authors.lastname: Tamvakopoulos
authors.affiliation: Department of Materials Science and Engineering, University of Ioannina, Ioannina 45110, Greece.
authors.forename: Demosthenes
authors.initials: D
authors.lastname: Fokas
authors.affiliation: Center for Clinical Research, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece; dvassilatis@bioacademy.gr thansp@hotmail.com.
authors.forename: Demetrios K
authors.initials: DK
authors.lastname: Vassilatis
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000978:Antiparkinson Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D004298:Dopamine / Q000235:genetics; D004355:Drug Stability; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D055503:Protein Multimerization; D051381:Rats; D047490:Retinoid X Receptor alpha / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000978:Antiparkinson Agents; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D047490:Retinoid X Receptor alpha; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine
keywords: Parkinson's disease; neuroprotection; target validation