Role of striatal-enriched protein tyrosine phosphatase STEP in the nigrostriatal pathway

• Autor(a) principal: Videira, Rita Alexandra Barreiros Domingos
• Data de Publicação: 2012
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.6/2867
• topic: Proteína fosfatase - Resíduos de tirosina; Neurónios dopaminérgicos

Protein tyrosine phosphorylation plays a central role in numerous neuronal processes. It has been implicated in axonal growth, synapse formation, cell-cell and cell-extracellular matrix interactions and differentiation. To regulate these processes, there is a balance between the level of phosphorylation caused by protein tyrosine kinases and the opposing action of protein tyrosine phosphatases. The striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase involved in neuronal signal transduction. STEP is present in high levels in medium spiny neurons of the striatum - the dopaminoceptive neurons - where it is regulated by dopamine receptors. STEP mRNA is alternatively spliced into the membrane-associated STEP61 and the cytosolic STEP46. Both isoforms are expressed in the striatum, whereas the other brain areas only express STEP61. STEP pathway is altered in some neurodegenerative diseases, however, there is no information on the expression of STEP in Parkinson’s disease (PD). PD is characterized by the progressive degeneration of dopaminergic neurons from the substantia nigra that project to the striatum resulting in reduced striatal levels of dopamine, a neurotransmitter that regulates STEP activity. In this way, the main goal of the present research activity was to determine if changes in dopaminergic signaling, resultant from a selective dopaminergic lesion in Parkinson’s disease models, can influence the expression of STEP in the nigrostriatal pathway. Besides the strong expression of STEP in the striatum, we observed that STEP is also expressed by midbrain dopaminergic neurons and its expression varies along development, however, the expression profile is different in both regions. With this work we intended to deepen if STEP expression is regulated by the dopaminergic lesion using PD models. Recurring to a cellular and mouse model of the disease, we observed that levels of STEP are increased in PD. For the determination of this effect, neuron-astrocytes midbrain co-cultures were previously stimulated with MPP+ and, in parallel, young adult C57BL/6 mice were submitted to an intraperitoneal injection of MPTP. The extension of the lesion was determined in both models by assessing both the number of dopaminergic neurons and the levels of tyrosine hydroxylase. Since MPTP is converted to MPP+ in astrocytes, we further investigated if midbrain astrocytes can be modified by these stimuli and we also evaluated if the changes in STEP expression were associated with increased reactivity of astrocytes. In vitro, we did not observe STEP expression in astrocytes. However, in vivo, we observed increased levels of a marker of astrocyte reactivity in the substantia nigra in parallel with increased levels of STEP. These studies indicate that there is a relation between STEP expression and dopaminergic lesion and, perhaps this relation may be critical for the pathogenesis of PD and therefore it can be considered a potential therapeutic target.