1. Murine dopaminergic Müller cells restore motor function in a model of Parkinson's disease
- Author
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Patrícia F. Gardino, Renata Fleming, Stevens K. Rehen, Daniel Veloso Cadilhe, Luis E. Santos, Bernardo Stutz, Ricardo Augusto de Melo Reis, Fernando G. de Mello, Phillip W. Dickson, Fabio Silva Lima da Conceição, Mariana Acquarone, Jean-Christophe Houzel, and Peter R. Dunkley
- Subjects
Cell type ,Tyrosine 3-Monooxygenase ,Dopamine ,Ependymoglial Cells ,Dopamine transport ,Mice, Transgenic ,Striatum ,Motor Activity ,Biology ,Biochemistry ,Mice ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Parkinsonian Disorders ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,medicine ,Animals ,Cebus ,Phosphorylation ,Neurotransmitter ,Cells, Cultured ,Retina ,Tyrosine hydroxylase ,Dopaminergic Neurons ,Dopaminergic ,Cell Differentiation ,Recovery of Function ,Corpus Striatum ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,chemistry ,Female ,sense organs ,Neuroscience ,medicine.drug - Abstract
Muller 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, Muller cells may undergo dedifferentiation, being able to generate other neural cell types. Here, we show that purified mouse Muller 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 Muller cells are able to synthesize and release dopamine to the extracellular medium. Moreover, Muller-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 Muller cells as a source of dopamine in cell therapy procedures, we used a mouse model of Parkinson's disease, in which mouse Muller 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 Muller cell grafting. Muller cells are the main glial cells in the retina. When these cells are cultured in the absence of neurons, they spontaneously express proteins of the dopaminergic phenotype, including the enzymes tyrosine hydroxylase (TH), L-DOPA-decarboxylase (DDC) and the dopamine transport system (DAT). In this study, we show this phenomenon is observed with Muller cells obtained from different species, including primates, and address the therapeutic potential of these cells, using a mouse model of Parkinson's disease (PD). ‘Dopaminergic Muller cells’ synthesize dopamine and release most of this neurotransmitter to the extracellular space, constituting a natural dopaminergic ‘pump’. When transplanted to the striatum of PD mice, Muller cells decreased their apomorphine-induced rotational behavior and restored their overall motor functions, measured by rotarod and forelimb use asymmetry tests. Local restoration of dopaminergic signaling was also observed in grafted PD mice, by measuring striatum dopamine and its metabolite (DOPAC) levels (SB: 20µm).
- Published
- 2013