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The extracellular matrix (ECM) critically affects β cell functions via integrin activation. But whether these ECM actions drive the spatial organization of β cells, as they do in epithelial cells, is unknown. Here, we show that within islets of Langerhans, focal adhesion activation in β cells occurs exclusively where they contact the capillary ECM (vascular face). In cultured β cells, 3D mapping shows enriched insulin granule fusion where the cells contact ECM-coated coverslips, which depends on β1 integrin receptor activation. Culture on micro-contact printed stripes of E-cadherin and fibronectin shows that β cell contact at the fibronectin stripe selectively activates focal adhesions and enriches exocytic machinery and insulin granule fusion. Culture of cells in high glucose, as a model of glucotoxicity, abolishes granule targeting. We conclude that local integrin activation targets insulin secretion to the islet capillaries. This mechanism might be important for islet function and may change in disease.

BackgroundATP13A2 (PARK9) loss of function mutations are a genetic cause of an early-onset form of Parkinson’s disease (PD), with in vitro studies showing that ATP13A2 deficits lead to lysosomal and mitochondrial dysfunction and α-synuclein accumulation, while elevated ATP13A2 expression reduces α-synuclein toxicity. The three human brain tissue studies assessing changes in ATP13A2 expression in PD produced divergent results; mRNA is increased while protein levels were observed to be either increased or decreased. This apparent conflict in protein levels might have arisen from examining Lewy body disease cases with coexisting Alzheimer-type pathologies.To assess whether ATP13A2 levels in Lewy body disease are modified by Alzheimer-type β-amyloid deposition, we evaluated cases of pure PD and pure dementia with Lewy bodies (DLB) for changes in ATP13A2, α-synuclein and β-amyloid protein levels in cortical regions with and without Lewy bodies.ResultsIn all Lewy body disease cases, we identified decreased ATP13A2 protein levels that correlated with increases in both α-synuclein and β-amyloid. Partial colocalization was observed between ATP13A2 and α-synuclein in Lewy bodies, whereas ATP13A2 did not colocalize with pathological β-amyloid deposition.ConclusionsOur data show that patients with Lewy body diseases have an overall deficit in ATP13A2 protein levels, with the remaining protein being more insoluble and partially redistributing towards Lewy bodies. This supports the concept that increasing ATP13A2 levels may offer potential therapeutic benefits to patients with Lewy body diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/2051-5960-1-11) contains supplementary material, which is available to authorized users.