title: Combined Nurr1 and Foxa2 roles in the therapy of Parkinson's disease.
abstract: Use of the physiological mechanisms promoting midbrain DA (mDA) neuron survival seems an appropriate option for developing treatments for Parkinson's disease (PD). mDA neurons are specifically marked by expression of the transcription factors Nurr1 and Foxa2. We show herein that Nurr1 and Foxa2 interact to protect mDA neurons against various toxic insults, but their expression is lost during aging and degenerative processes. In addition to their proposed cell-autonomous actions in mDA neurons, forced expression of these factors in neighboring glia synergistically protects degenerating mDA neurons in a paracrine mode. As a consequence of these bimodal actions, adeno-associated virus (AAV)-mediated gene delivery of Nurr1 and Foxa2 in a PD mouse model markedly protected mDA neurons and motor behaviors associated with nigrostriatal DA neurotransmission. The effects of the combined gene delivery were dramatic, highly reproducible, and sustained for at least 1 year, suggesting that expression of these factors is a promising approach in PD therapy.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea.
authors.forename: Sang-Min
authors.initials: SM
authors.lastname: Oh
authors.affiliation: Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea.
authors.forename: Mi-Yoon
authors.initials: MY
authors.lastname: Chang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea.
authors.forename: Jae-Jin
authors.initials: JJ
authors.lastname: Song
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea.
authors.forename: Yong-Hee
authors.initials: YH
authors.lastname: Rhee
authors.affiliation: Department of Phamacology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Joe
authors.affiliation: Department of Applied Bioscience, College of Life Science, CHA University, Seoul, Korea.
authors.forename: Hyun-Seob
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea sanghooni@hanmail.net leesh@hanyang.ac.kr.
authors.forename: Sang-Hoon
authors.initials: SH
authors.lastname: Yi
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea sanghooni@hanmail.net leesh@hanyang.ac.kr.
authors.forename: Sang-Hun
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000502:physiology*; D015316:Genetic Therapy / Q000379:methods*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008636:Mesencephalon / Q000473:pathology*; D008813:Mice, Inbred ICR; D009457:Neuroglia / Q000502:physiology; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000473:pathology* / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: C496503:Foxa2 protein, mouse; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D051542:Hepatocyte Nuclear Factor 3-beta
keywords: Foxa2; Nurr1; Parkinson's disease; gene therapy; midbrain dopamine neuron