RESUMEN
Phospho-Ser129 α-synuclein is the modified form of α-synuclein that occurs most frequently within Parkinson's disease pathological inclusions. Here we demonstrate that the antidiabetic drug metformin significantly reduces levels of phospho-Ser129 α-synuclein and the ratio of phospho-Ser129 α-synuclein to total α-synuclein. This effect was documented in vitro in SH-SY5Y and HeLa cells as well as in primary cultures of hippocampal neurons. In vitro work also elucidated the mechanisms underlying metformin's action. Following metformin exposure, decreased phospho-Ser129 α-synuclein was not strictly dependent on induction of AMP-activated protein kinase, a primary target of the drug. On the other hand, metformin-induced phospho-Ser129 α-synuclein reduction was consistently associated with inhibition of mammalian target of rapamycin (mTOR) and activation of protein phosphatase 2A (PP2A). Evidence supporting a key role of mTOR/PP2A signaling included the finding that, similar to metformin, the canonical mTOR inhibitor rapamycin was capable of lowering the ratio of phospho-Ser129 α-synuclein to total α-synuclein. Furthermore, no decrease in phosphorylated α-synuclein occurred with either metformin or rapamycin when phosphatase activity was inhibited, supporting a direct relationship between mTOR inhibition, PP2A activation and protein dephosphorylation. A final set of experiments confirmed the effectiveness of metformin in vivo in wild-type C57BL/6 mice. Addition of the drug to food or drinking water lowered levels of phospho-Ser129 α-synuclein in the brain of treated animals. These data reveal a new mechanism leading to α-synuclein dephosphorylation that could be targeted for therapeutic intervention by drugs like metformin and rapamycin.
Asunto(s)
Hipocampo/efectos de los fármacos , Metformina/farmacología , Neuronas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteína Fosfatasa 2/metabolismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , alfa-Sinucleína/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Activación Enzimática , Edad Gestacional , Células HeLa , Hipocampo/embriología , Hipocampo/enzimología , Hipocampo/patología , Humanos , Hipoglucemiantes/farmacología , Ratones , Ratones Endogámicos C57BL , Neuronas/enzimología , Neuronas/patología , Fosforilación , Cultivo Primario de Células , Serina , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Factores de Tiempo , Transfección , alfa-Sinucleína/genéticaRESUMEN
The relationship between tobacco consumption and psychiatric disorders is a widely discussed topic that is generating a considerable yet controversial bibliography, that can be approached from different points of view. The authors make a revision and critical evaluation about smoking prevalence on psychiatric population, in the different psychiatric disorders and discussing the theories implicated.