Expression of Tyrosine Hydroxylase is Negatively Regulated Via Prion Protein
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Cellular prion protein (PrPC) is a glycoprotein of the plasma membrane that plays pleiotropic functions by interacting with multiple signaling complexes at the cell surface. Recently, a number of studies have reported the involvement of PrPC in dopamine metabolism and signaling, including its interactions with tyrosine hydroxylase (TH) and dopamine receptors. However, the outcomes reported by independent studies are still debatable. Therefore in this study, we investigated the effects of PrPC on the TH expression during the differentiation of N2a cells with dibutyryl-cAMP, a well-known cAMP analog that activates TH transcription. Upon differentiation, TH was induced with concomitant reduction of PrPC at protein level, but not at mRNA level. shRNA-mediated PrPC reduction increased the basal level of TH at both mRNA and protein levels without dibutyryl-cAMP treatment. This phenotype was reversed by re-expression of PrPC. PrPC knockdown also potentiated the effect of dibutyryl-cAMP on TH expression. Our findings suggest that PrPC has suppressive effects on TH expression. As a consequence, altered PrPC functions may affect the regulation of dopamine metabolism and related neurological disorders.
KeywordsCellular prion protein Dopamine metabolism Tyrosine hydroxylase Gene expression
This study was supported by Grants from FAPESP [Fundação de Amparo à Pesquisa do Estado de São Paulo: 2013/22413-5 (K.S.L); 2013/07937-8 (I.G)], CAPES (Coordenação de Aperfeiçoamento de pessoal de Nível Superior), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico: 467566/2014-3) and EMU (programa de equipamentos multiusuários). We thank Dr. Ricardo Borges Machado from UNIFESP, who carried out the quantification of dopamine and its metabolites.
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Conflict of interest
None of the authors have any conflict of interests to disclose.
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