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

Abstract

α-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 α-synuclein have been shown to propagate between neurons in a prion-like manner, although the mechanism by which α-synuclein transfer induces degeneration remains to be identified. Due to this evidence extracellular α-synuclein is now considered a critical target to hinder disease progression in Parkinson's disease. Given the importance of extracellular α-synuclein levels, we have now investigated the molecular pathway of α-synuclein secretion in mouse brain. To this end, we have identified a novel synaptic network that regulates α-synuclein release in mouse striatum. In this brain area, the majority of α-synuclein is localized in corticostriatal glutamatergic terminals. Absence of α-synuclein from the lumen of brain-isolated synaptic vesicles suggested that they are unlikely to mediate its release. To dissect the mechanism of α-synuclein release, we have used reverse microdialysis to locally administer reagents that locally target specific cellular pathways. Using this approach, we show that α-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 α-synuclein release from the glutamatergic terminals through activation of the presynaptic GABAB receptors. Considering that sulfonylurea receptors can be selectively targeted, our study highlights the potential use of the key molecules in the α-synuclein secretory pathway to aid the discovery of novel therapeutic interventions for Parkinson's disease.

A Cortical Pathogenic Theory of Parkinson’s Disease

“…Mitochondrial dysfunction has been associated with alpha-synuclein aggregation and degeneration of the nigrostriatal projection (Mullin and Schapira, 2013). Interestingly, in both wild-type and alpha-synuclein overexpressing transgenic mice, a substantial amount-if not the majority-of physiological alpha-synuclein in the striatum is localized at corticostriatal glutamatergic terminals (Totterdell and Meredith, 2005;Taguchi et al, 2016;Emmanouilidou et al, 2016; Figures 2A and 2B). Conversely, virtually no alpha-synuclein is detected in the cell bodies of the output cortical layers V and VI (Taguchi et al, 2016), and, importantly, relatively little alpha-synclein is localized at thalamostriatal and nigrostriatal terminals (Emmanouilidou et al, 2016; Figure 2B).…”

How strong is the evidence that Parkinson's disease is a prion disorder?

“…It is important to emphasize that underlying mechanisms differ depending on whether the α-synuclein is present as a monomer, oligomer or fibril. A recent in vivo study indicated that monomeric α-synuclein is released from nerve terminals in the striatum in a process that is potassium-dependent and regulated by presynaptic GABA receptors (65). Monomers of α-synuclein appear to readily translocate across cellular membranes in a temperature-insensitive manner (22).…”

Exocytosis and Spreading of Normal and Aberrant α‐Synuclein

“…Such a regulatory cascade would be expected given the high organization complexity of the specific neuronal networks. Of note, since neuronal communication is orchestrated by neurotransmitter release, this work also suggested that neurotransmitters could play a significant role in α‐synuclein secretion in vivo . This would be of critical importance in neurodegenerative diseases, such as Parkinson's disease, where loss of dopamine dramatically alters the firing pattern of neurons that receive dopamine input in other brain areas including the striatum and the cortex .…”

“…Even though the association of α‐synuclein with SVs has been reported, it is still unclear how the protein reaches and is incorporated in the membrane of SVs. Most importantly, recent data indicated that SVs do not seem to be involved in the secretion of α‐synuclein .…”

“…In the molecular level, we could hypothesize that regulation of the release would be the outcome from the mobilization of intracellular molecular cascades within the neuron. To this end, our recent work highlights the fact that α‐synuclein secretion not only results from the co‐operation of several molecular players within the secretory neuron but also its regulation indeed requires the crosstalk of different neurons and terminals present in a certain brain region, in this case the striatum. Such a regulatory cascade would be expected given the high organization complexity of the specific neuronal networks.…”