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  • Role of STEP in dopaminergic synapses
    Publication . Teixeira, Emika Calado; Baltazar, Graça Maria Fernandes
    Striatal-enriched protein tyrosine phosphatase (STEP) is a member of the PTP family, and exists in two major isoforms, STEP61 and STEP46, being differentially expressed during development. STEP is known to oppose synaptic strengthening by the dephosphorylation of key molecules involved in neuronal signaling. Most of the published works on STEP activity and regulation focus on its postsynaptic role, but recently STEP has also been located in glutamatergic presynaptic terminals where it contributes to the regulation of calcium levels. Concerning dopaminergic systems, it was reported that STEP levels are increased in Parkinson’ disease (PD) mice model and in parkin-mutated PD patients. A parkin mutation may lead to STEP accumulation, which may contribute to PD-associated dopaminergic neuronal death. PD is an idiopathic pathology characterized by motor dysfunction due to the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Reported data show high levels of tyrosine hydroxylase (TH), THSer31 phosphorylation and increased dopamine levels in striatum of STEP KO mice, suggesting that STEP acts as a repressor of dopaminergic transmission. Additionally, STEP KO mice or wild type (WT) mice treated with a specific STEP inhibitor shown increased resistance to the dopaminergic toxin MPTP. This work aims to explore if presynaptic STEP affects the formation and function of dopaminergic synapses. Our data showed that dopaminergic neurons express STEP at the presynaptic terminals and STEP inhibition did not significantly increase the levels of presynaptic markers in neuron cultures from mice midbrain. The specific evaluation of dopaminergic neurons showed that STEP inhibition does not affect synaptophysin levels. The morphological data suggest a compensation effect when the dopaminergic toxin was administrated. The reduction of dopaminergic cells may lead to an increase in the number of neurites to compensate the lack of dopaminergic transmission. Taking together, more studies are necessary to clarify the role played by presynaptic STEP in dopaminergic neurons and whereas presynaptic STEP contributes to retrograde cell death observed in PD pathology.
    2019-11-15Master thesis Open access Show more