Mutations in the human VPS13 genes are responsible for neurodevelopmental and neurodegenerative disorders including chorea acanthocytosis (VPS13A) and Parkinson's disease (VPS13C). The mechanisms of these diseases are unknown. Genetic studies in yeast hinted that Vps13 may have a role in lipid exchange between organelles. In this study, we show that the N-terminal portion of VPS13 is tubular, with a hydrophobic cavity that can solubilize and transport glycerolipids between membranes. We also show that human VPS13A and VPS13C bind to the ER, tethering it to mitochondria (VPS13A), to late endosome/lysosomes (VPS13C), and to lipid droplets (both VPS13A and VPS13C). These findings identify VPS13 as a lipid transporter between the ER and other organelles, implicating defects in membrane lipid homeostasis in neurological disorders resulting from their mutations. Sequence and secondary structure similarity between the N-terminal portions of Vps13 and other proteins such as the autophagy protein ATG2 suggest lipid transport roles for these proteins as well.
Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression to compute PrediXcan (a gene mapping approach) results using summary data (S-PrediXcan) and show its accuracy and general robustness to misspecified reference sets. We apply this framework to 44 GTEx tissues and 100+ phenotypes from GWAS and meta-analysis studies, creating a growing public catalog of associations that seeks to capture the effects of gene expression variation on human phenotypes. Replication in an independent cohort is shown. Most of the associations are tissue specific, suggesting context specificity of the trait etiology. Colocalized significant associations in unexpected tissues underscore the need for an agnostic scanning of multiple contexts to improve our ability to detect causal regulatory mechanisms. Monogenic disease genes are enriched among significant associations for related traits, suggesting that smaller alterations of these genes may cause a spectrum of milder phenotypes.
14To understand the biological mechanisms underlying the thousands of genetic variants robustly associated with 15 complex traits, scalable methods that integrate GWAS and functional data generated by large-scale efforts are 16 needed. We derived a mathematical expression to compute PrediXcan results using summary data (S-17 PrediXcan) and showed its accuracy and robustness to misspecified reference populations. We compared S-18PrediXcan with existing methods and combined them into a best practice framework (MetaXcan) that 19integrates GWAS with QTL studies and reduces LD-confounded associations. We applied this framework to 44 20 GTEx tissues and 101 phenotypes from GWAS and meta-analysis studies, creating a growing catalog of 21 associations that captures the effects of gene expression variation on human phenotypes. Most of the 22 associations were tissue specific, indicating context specificity of the trait etiology. Colocalized significant 23 associations in unexpected tissues underscore the advantages of an agnostic scanning of multiple contexts to 24 increase the probability of detecting causal regulatory mechanisms. 25Prediction models, efficient software implementation, and association results are shared as a resource for 26 the research community.
INTRODUCTION Insulin is secreted by pancreatic β cells in response to glucose stimulation. Its release is controlled by the interplay of calcium and phosphoinositide signaling pathways. A rapid release phase, in which insulin containing granules that are already docked and primed at the plasma membrane (PM) undergo exocytosis, is followed by slow release. In this second phase, granules are docked and primed and then released in a series of bursts, each triggered by a spike in cytosolic Ca2+. RATIONALE To better understand the molecular basis underlying insulin secretion, we characterized TMEM24, a protein enriched in neuroendocrine cells previously suggested to be required for a normal secretory response. RESULTS We found that TMEM24 is an endoplasmic reticulum (ER) protein that concentrates at ER-PM contact sites, where it tethers the two bilayers. TMEM24 binding “in trans” to the PM is negatively regulated by phosphorylation in response to elevation of cytosolic Ca2+, so that TMEM24 transiently dissociates from the PM as Ca2+ concentration spikes and then reassociates with this membrane upon dephosphorylation. Additionally, TMEM24 contains a lipid transport module of the synaptotagmin-like, mitochondrial and lipid-binding protein (SMP) family, which we structurally characterized and showed to bind glycerolipids with a preference for phosphatidylinositol (PI). Thus, TMEM24 helps deliver PI, which is synthesized in the ER, to the PM, where it is converted to phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to replenish pools of this lipid hydrolyzed during glucose-stimulated signaling. Supporting a key role of TMEM24 in the coordination of Ca2+ and phosphoinositide signaling, the lipid transport function of TMEM24 is essential for sustaining the intracellular Ca2+ oscillations that trigger bursts of insulin granule release and hence insulin secretion. PI(4,5)P2 is required for Ca2+-dependent exocytosis. It also controls the activity of PM ion channels that regulate cytosolic Ca2+ levels and is the precursor of IP3, which also helps to modulate cytosolic Ca2+ by triggering Ca2+ release from the ER. Thus, in insulin-secreting cells, TMEM24 participates in coordinating Ca2+ and phosphoinositide signaling pathways to cause pulsatile insulin secretion (see the figure). CONCLUSION Our findings implicate ER-PM contact sites and an ER resident lipid-transfer protein in the direct regulation of PM phosphoinositide pools, offering fresh insights into the mechanisms of cellular phosphoinositide dynamics. More specifically, they elaborate the mechanisms underlying insulin secretion, which is impaired in patients with type II diabetes, and may ultimately have therapeutic ramifications. TMEM24 activity cycle at ER-PM contacts Glucose stimulation of insulin-secreting cells triggers Ca2+ influx, phospholipase C–dependent PI(4,5)P2 cleavage, and granule exocytosis. Ca2+-stimulated phosphorylation causes TMEM24 dissociation from the PM and interruption of SMP-mediated PI transfer that allows PI(4,5)P2 resynthesis. Lower...
SUMMARY Synaptojanin 1 (SJ1) is a major presynaptic phosphatase that couples synaptic vesicle endocytosis to the dephosphorylation of PI(4,5)P2, a reaction needed for the shedding of endocytic factors from their membranes. While the role of SJ1’s 5-phosphatase module in this process is well established, the contribution of its Sac phosphatase domain, whose preferred substrate is PI4P, remains unclear. Recently a homozygous mutation in its Sac domain was identified in early-onset Parkinsonism patients. We show that mice carrying this mutation developed neurological manifestations similar to those of human patients. Synapses of these mice displayed endocytic defects and a striking accumulation of clathrin coated intermediates strongly implicating Sac domain’s activity in endocytic protein dynamics. Mutant brains had elevated auxilin (PARK19) and parkin (PARK2) levels. Moreover, dystrophic axonal terminal changes were selectively observed in dopaminergic axons in the dorsal striatum. These results strengthen evidence for a link between synaptic endocytic dysfunction and Parkinson’s disease.
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