GABA transmission via ATP-dependent K+ channels regulates α-synuclein secretion in mouse striatum

Extracellular alpha-synuclein is considered a critical target for hindering disease progression in Parkinson's disease. Emmanouilidou et al. identify a synaptic network that regulates alpha-synuclein release in mouse striatum via modulation of GABAergic transmission. Targeting the key players in this pathway, which include sulfonylurea receptors, may have therapeutic benefits in synucleinopathies.Extracellular alpha-synuclein is considered a critical target for hindering disease progression in Parkinson's disease. Emmanouilidou et al. identify a synaptic network that regulates alpha-synuclein release in mouse striatum via modulation of GABAergic transmission. Targeting the key players in this pathway, which include sulfonylurea receptors, may have therapeutic benefits in synucleinopathies.alpha-Synuclein is readily released in human and mouse brain parenchyma, even though the normal function of the secreted protein has not been yet elucidated. Under pathological conditions, such as in Parkinson's disease, pathologically relevant species of alpha-synuclein have been shown to propagate between neurons in a prion-like manner, although the mechanism by which alpha-synuclein transfer induces degeneration remains to be identified. Due to this evidence extracellular alpha-synuclein is now considered a critical target to hinder disease progression in Parkinson's disease. Given the importance of extracellular alpha-synuclein levels, we have now investigated the molecular pathway of alpha-synuclein secretion in mouse brain. To this end, we have identified a novel synaptic network that regulates alpha-synuclein release in mouse striatum. In this brain area, the majority of alpha-synuclein is localized in corticostriatal glutamatergic terminals. Absence of alpha-synuclein from the lumen of brain-isolated synaptic vesicles suggested that they are unlikely to mediate its release. To dissect the mechanism of alpha-synuclein release, we have used reverse microdialysis to locally administer reagents that locally target specific cellular pathways. Using this approach, we show that alpha-synuclein secretion in vivo is a calcium-regulated process that depends on the activation of sulfonylurea receptor 1-sensitive ATP-regulated potassium channels. Sulfonylurea receptor 1 is distributed in the cytoplasm of GABAergic neurons from where the ATP-dependent channel regulates GABA release. Using a combination of specific agonists and antagonists, we were able to show that, in the striatum, modulation of GABA release through the sulfonylurea receptor 1-regulated ATP-dependent potassium channels located on GABAergic neurons controls alpha-synuclein release from the glutamatergic terminals through activation of the presynaptic GABA(B) receptors. Considering that sulfonylurea receptors can be selectively targeted, our study highlights the potential use of the key molecules in the alpha-synuclein secretory pathway to aid the discovery of novel therapeutic interventions for Parkinson's disease.