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.
Woman with right abdominal pain Hancock‐Cerutti, William; Aliaga, Leonardo
Journal of the American College of Emergency Physicians Open,
February 2023, Letnik:
4, Številka:
1
Journal Article
...a number of groups have recently elucidated unexpected phenotypic associations with certain genetic variants found in genome-wide association studies for other traits (13-16).
The evolutionarily conserved VPS13 family proteins have been implicated in several cellular processes. Mutations in each of the four human VPS13s cause neurodevelopmental or neurodegenerative ...disorders. Until recently, the molecular function of VPS13 remained elusive. Genetic, functional and structural studies have now revealed that VPS13 acts at contact sites between intracellular organelles to transport lipids by a novel mechanism: direct transfer between bilayers via a hydrophobic channel that spans its entire rod-like N-terminal half. Predicted similarities to the autophagy protein ATG2 suggested a similar role for ATG2 that has now been confirmed by structural and functional studies. Here, after a brief review of this evidence, we discuss what is known of human VPS13 proteins in physiology and disease.
High-density lipoprotein cholesterol (HDL-C) is thought to be atheroprotective yet some patients with elevated HDL-C levels develop cardiovascular disease, possibly due to the presence of ...dysfunctional HDL. We aimed to assess the metabolic fate of circulating HDL particles in patients with high HDL-C with and without coronary artery disease (CAD) using in vivo dual labeling of its cholesterol and protein moieties. We measured HDL apolipoprotein (apo) A-I, apoA-II, free cholesterol (FC), and cholesteryl ester (CE) kinetics using stable isotope-labeled tracers (D3-leucine and 13C2-acetate) as well as ex vivo cholesterol efflux to HDL in subjects with (n = 6) and without (n = 6) CAD that had HDL-C levels >90th percentile. Healthy controls with HDL-C within the normal range (n = 6) who underwent the same procedures were used as the reference. Subjects with high HDL-C with and without CAD had similar plasma lipid levels and similar apoA-I, apoA-II, HDL FC, and CE pool sizes with no significant differences in fractional clearance rates (FCRs) or production rates (PRs) of these components between groups. Subjects with high HDL-C with and without CAD also had similar basal and cAMP-stimulated ex vivo cholesterol efflux to HDL. When all subjects were considered (n = 18), unstimulated non-ABCA1-mediated efflux (but not ABCA1-specific efflux) was correlated positively with apoA-I production (r = 0.552, p = 0.017) and HDL FC and CE pool sizes, and negatively with the fractional clearance rate of FC (r = −0.759, p = 4.1 × 10−4) and CE (r = −0.652, p = 4.57 × 10−3). Our data are consistent with the concept that ex vivo non-ABCA1 efflux capacity may correlate with slower in vivo turnover of HDL cholesterol moieties. The use of a dual labeling protocol provided for the first time the opportunity to assess the association of ex vivo cholesterol efflux capacity with in vivo HDL cholesterol metabolic parameters.
Medical education is lagging behind advances in planetary health knowledge due to the considerable barriers to introducing new topics into medical curricula. This potentially leaves doctors of the ...future ill-equipped to deal with the health challenges associated with environmental degradation. The recently conceived ‘infusion’ approach by the Icahn School of Medicine at Mount Sinai, New York, USA, represents a promising method for integrating planetary health topics into medical education. Adopting this approach, the International Medical Education Collaboration on Climate and Sustainability (IMECCS) was founded, with the goal of empowering healthcare students and faculty members worldwide to integrate planetary health education into their curricula.
IMECCS consists of medical students and faculty members at universities in the USA, UK, and Honduras with experience in introducing planetary health topics into medical curricula. Based on discussions of challenges and successes, the group created an online open-access resource bank designed to enable a medical student or faculty member, without prior experience, to implement a planetary health curriculum and infuse these topics into existing teaching sessions at their institution.
VPS13 is a eukaryotic lipid transport protein localized at membrane contact sites. Previous studies suggested that it may transfer lipids between adjacent bilayers by a bridge-like mechanism. Direct ...evidence for this hypothesis from a full-length structure and from electron microscopy (EM) studies in situ is still missing, however. Here, we have capitalized on AlphaFold predictions to complement the structural information already available about VPS13 and to generate a full-length model of human VPS13C, the Parkinson's disease-linked VPS13 paralog localized at contacts between the endoplasmic reticulum (ER) and endo/lysosomes. Such a model predicts an ∼30-nm rod with a hydrophobic groove that extends throughout its length. We further investigated whether such a structure can be observed in situ at ER-endo/lysosome contacts. To this aim, we combined genetic approaches with cryo-focused ion beam (cryo-FIB) milling and cryo-electron tomography (cryo-ET) to examine HeLa cells overexpressing this protein (either full length or with an internal truncation) along with VAP, its anchoring binding partner at the ER. Using these methods, we identified rod-like densities that span the space separating the two adjacent membranes and that match the predicted structures of either full-length VPS13C or its shorter truncated mutant, thus providing in situ evidence for a bridge model of VPS13 in lipid transport.
Mutations in VPS13C cause early-onset, autosomal recessive Parkinson's disease (PD). We have established that VPS13C encodes a lipid transfer protein localized to contact sites between the ER and ...late endosomes/lysosomes. In the current study, we demonstrate that depleting VPS13C in HeLa cells causes an accumulation of lysosomes with an altered lipid profile, including an accumulation of di-22:6-BMP, a biomarker of the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation. In addition, the DNA-sensing cGAS-STING pathway, which was recently implicated in PD pathogenesis, is activated in these cells. This activation results from a combination of elevated mitochondrial DNA in the cytosol and a defect in the degradation of activated STING, a lysosome-dependent process. These results suggest a link between ER-lysosome lipid transfer and innate immune activation in a model human cell line and place VPS13C in pathways relevant to PD pathogenesis.
Biallelic loss-of-function mutations in VPS13C cause early-onset Parkinson’s Disease (PD), and the VPS13C locus is a GWAS hit for sporadic PD risk. VPS13C is a member of the VPS13 family, which in ...humans contains three other proteins, VPS13A, VPS13B, and VPS13D, all with ties to neurological diseases. Mutations in VPS13A cause chorea-acanthocytosis a Huntington’s like syndrome with dysmorphic erythrocytes, mutations in VPS13B cause the neurodevelopmental disorder Cohen syndrome, and mutations in VPS13D cause spastic ataxia with varying presentation. The molecular function of these proteins, why their loss cause neurological diseases, and why they are each associated with distinct diseases despite their homology have all been open questions. In yeast, the single Vps13 protein localizes to contact sites between the mitochondria and vacuole, the yeast lysosome, and at the nuclear-vacuolar junction (NVJ), where multiple lines of indirect evidence has hinted that it may play a role in lipid transfer between these organelles. To understand whether human VPS13 proteins have diverged in their subcellular localization, we employed a combination of light and electron microscopy to demonstrate that VPS13A localizes to contact sites between the endoplasmic reticulum (ER) and mitochondria, while VPS13C localizes to contact sites between the ER and late endosomes/lysosomes. Both proteins also share a localization at ER-lipid droplet contact sites. We further show that the N-terminal portion of VPS13 forms a novel, tubular, hydrophobic cavity that can solubilize and transport glycerolipids between membranes. 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 suggested lipid transport roles for these proteins as well, which has since been demonstrated. We next investigated the cellular phenotypes of VPS13C loss-of-function in an attempt to shed light on the pathophysiology of VPS13C-associated PD. We used CRISPR-Cas9 to generate VPS13C-knockout (VPS13CKO) HeLa cells. These cells have more lysosomes compared to WT, with accumulation of both membrane and luminal lysosomal proteins. These lysosomes have an altered lipid profile, including a substantial decrease in ether-linked phospholipids and an accumulation of di-22:6-BMP, a biomarker of the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation. In addition, the DNA-sensing cGAS/STING pathway, which was recently implicated in PD pathogenesis, is activated in these cells. This activation results from a combination of elevated mitochondrial DNA in the cytosol and a defect in the degradation of activated STING, a lysosome-dependent process. These results suggest a link between ER-lysosome lipid transfer and innate immune activation and place VPS13C in pathways relevant to PD pathogenesis. Further exploration of these pathways has the potential to yield new mechanistic understanding and novel therapeutic strategies for this debilitating illness.
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