title: Murine dopaminergic Müller cells restore motor function in a model of Parkinson's disease.
abstract: Müller cells constitute the main glial cell type in the retina where it interacts with virtually all cells displaying relevant functions to retinal physiology. Under appropriate stimuli, Müller cells may undergo dedifferentiation, being able to generate other neural cell types. Here, we show that purified mouse Müller cells in culture express a group of proteins related to the dopaminergic phenotype, including the nuclear receptor-related 1 protein, required for dopaminergic differentiation, as well the enzyme tyrosine hydroxylase. These dopaminergic components are active, since Müller cells are able to synthesize and release dopamine to the extracellular medium. Moreover, Müller-derived tyrosine hydroxylase can be regulated, increasing its activity because of phosphorylation of serine residues in response to agents that increase intracellular cAMP levels. These observations were extended to glial cells obtained from adult monkey retinas with essentially the same results. To address the potential use of dopaminergic Müller cells as a source of dopamine in cell therapy procedures, we used a mouse model of Parkinson's disease, in which mouse Müller cells with the dopaminergic phenotype were transplanted into the striatum of hemi-parkinsonian mice generated by unilateral injection of 6-hydroxydopamine. These cells fully decreased the apomorphine-induced rotational behavior and restored motor functions in these animals, as measured by the rotarod and the forelimb-use asymmetry (cylinder) tests. The data indicate local restoration of dopaminergic signaling in hemi-parkinsonian mice confirmed by measurement of striatal dopamine after Müller cell grafting.
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Stutz
authors.forename: Fabio Silva Lima
authors.initials: FS
authors.lastname: da Conceição
authors.forename: Luís Eduardo
authors.initials: LE
authors.lastname: Santos
authors.forename: Daniel Veloso
authors.initials: DV
authors.lastname: Cadilhe
authors.forename: Renata L
authors.initials: RL
authors.lastname: Fleming
authors.forename: Mariana
authors.initials: M
authors.lastname: Acquarone
authors.forename: Patrícia F
authors.initials: PF
authors.lastname: Gardino
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: de Melo Reis
authors.forename: Phillip W
authors.initials: PW
authors.lastname: Dickson
authors.forename: Peter R
authors.initials: PR
authors.lastname: Dunkley
authors.forename: Stevens
authors.initials: S
authors.lastname: Rehen
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Houzel
authors.forename: Fernando G
authors.initials: FG
authors.lastname: de Mello
mesh_terms: D000818:Animals; D002428:Cebus; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000502:physiology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D063928:Ependymoglial Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D020127:Recovery of Function / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine
keywords: Müller cells; Parkinson's disease; TH; cell therapy; dopamine