A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane.

Chorea-acanthocytosis (ChAc) and McLeod syndrome are diseases with shared clinical manifestations caused by mutations in VPS13A and XK, respectively. Key features of these conditions are the degeneration of caudate neurons and the presence of abnormally shaped erythrocytes. XK belongs to a family of plasma membrane (PM) lipid scramblases whose action results in exposure of PtdSer at the cell surface. VPS13A is an endoplasmic reticulum (ER)-anchored lipid transfer protein with a putative role in the transport of lipids at contacts of the ER with other membranes. Recently VPS13A and XK were reported to interact by still unknown mechanisms. So far, however, there is no evidence for a colocalization of the two proteins at contacts of the ER with the PM, where XK resides, as VPS13A was shown to be localized at contacts between the ER and either mitochondria or lipid droplets. Here we show that VPS13A can also localize at ER-PM contacts via the binding of its PH domain to a cytosolic loop of XK, that such interaction is regulated by an intramolecular interaction within XK, and that both VPS13A and XK are highly expressed in the caudate neurons. Binding of the PH domain of VPS13A to XK is competitive with its binding to intracellular membranes that mediate other tethering functions of VPS13A. Our findings support a model according to which VPS13A-dependent lipid transfer between the ER and the PM is coupled to lipid scrambling within the PM. They raise the possibility that defective cell surface exposure of PtdSer may be responsible for neurodegeneration.

Analysis of Brain, Blood, and Testis Phenotypes Lacking the Vps13a Gene in C57BL/6N Mice.

The Vps13a gene encodes a lipid transfer protein called VPS13A, or chorein, associated with mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), mitochondria-endosomes, and lipid droplets. This protein plays a crucial role in inter-organelle communication and lipid transport. Mutations in the VPS13A gene are implicated in the pathogenesis of chorea-acanthocytosis (ChAc), a rare autosomal recessive neurodegenerative disorder characterized by chorea, orofacial dyskinesias, hyperkinetic movements, seizures, cognitive impairment, and acanthocytosis. Previous mouse models of ChAc have shown variable disease phenotypes depending on the genetic background. In this study, we report the generation of a Vps13a flox allele in a pure C57BL/6N mouse background and the subsequent creation of Vps13a knockout (KO) mice via Cre-recombination. Our Vps13a KO mice exhibited increased reticulocytes but not acanthocytes in peripheral blood smears. Additionally, there were no significant differences in the GFAP- and Iba1-positive cells in the striatum, the basal ganglia of the central nervous system. Interestingly, we observed abnormal spermatogenesis leading to male infertility. These findings indicate that Vps13a KO mice are valuable models for studying male infertility and some hematological aspects of ChAc.

XK-Associated McLeod Syndrome: Nonhematological Manifestations and Relation to VPS13A Disease.

BACKGROUND: McLeod syndrome (MLS) is an X-linked multisystemic progressive disorder caused by loss of function mutations in the XK gene. The rare blood group phenotype of MLS patients with absent Kx antigen requires the support of specialized transfusion institutions because of the risk of transfusion complications. Acanthocytosis of red blood cells occurs in almost all patients. Nonhematological manifestations of MLS are very similar to those of VPS13A disease (chorea-acanthocytosis), an autosomal-recessive condition. Their shared phenotype apart from acanthocytosis includes movement disorders such as chorea and dystonia, epilepsy, peripheral neuropathy, and muscle involvement, typically with creatine kinase (CK) elevation, cardiomyopathy included. SUMMARY: In this review, we describe the nonhematological manifestations of MLS in comparison with those of VPS13A disease. While there are many similarities, differences such as mode of inheritance, sex distribution, age at manifestation, severity of heart involvement, frequency of feeding dystonia or of involuntary head drops may help to distinguish these disorders in the clinic. Immunohematological demonstration of the McLeod-Kell phenotype or detection of pathogenic mutations of XK (or VPS13A, respectively) is the gold standard for distinction. "Neuroacanthocytosis" was often used as an overarching term, but is potentially misleading, as the term does not refer to a defined disease entity. Its use, if continued, must not prevent clinicians to seek a final diagnosis on the basis of molecular findings. The clinical similarity of MLS and VPS13A disease has long suggested some shared pathophysiology. Evidence for molecular interaction between XK, the McLeod protein, and chorein, the VPS13A gene product, has recently been put forward: XK forms a complex with chorein/VPS13A, a bulk lipid transporter located at various membrane contact sites. The exact role of XK in this complex needs to be further elucidated. Impairment of bulk lipid transport appears as the common denominator of both MLS and VPS13A disease. A variety of further conditions may in time be added to the "bulk lipid transport diseases," such as the recently recognized disorders caused by mutations in the VPS13B, VPS13C, and VPS13D genes. KEY MESSAGES: (1) Patients diagnosed with the rare red cell McLeod phenotype (McLeod syndrome, MLS) require interdisciplinary collaboration of transfusion medicine specialists, neurologists, and cardiologists for both their hematological and nonhematological disease manifestations. (2) The phenotypical similarity of MLS and VPS13A disease, often leading to either confusion or insufficient diagnostic depth (under the label of "neuroacanthocytosis"), is based on interaction of the respective proteins, XK and chorein, within the cellular machinery for bulk lipid transport. (3) Overall, the term "bulk lipid transport diseases" seems useful for further research on a group of conditions that may not only share pathophysiology, but may also share treatment approaches.

Yeast and other lower eukaryotic organisms for studies of Vps13 proteins in health and disease.

Human Vps13 proteins are associated with several diseases, including the neurodegenerative disorder Chorea-acanthocytosis (ChAc), yet the biology of these proteins is still poorly understood. Studies in Saccharomyces cerevisiae, Dictyostelium discoideum, Tetrahymena thermophila and Drosophila melanogaster point to the involvement of Vps13 in cytoskeleton organization, vesicular trafficking, autophagy, phagocytosis, endocytosis, proteostasis, sporulation and mitochondrial functioning. Recent findings show that yeast Vps13 binds to phosphatidylinositol lipids via 4 different regions and functions at membrane contact sites, enlarging the list of Vps13 functions. This review describes the great potential of simple eukaryotes to decipher disease mechanisms in higher organisms and highlights novel insights into the pathological role of Vps13 towards ChAc.

Inhibition of Lithium Sensitive Orai1/ STIM1 Expression and Store Operated Ca2+ Entry in Chorea-Acanthocytosis Neurons by NF-κB Inhibitor Wogonin.

BACKGROUND/AIMS: The neurodegenerative disease Chorea-Acanthocytosis (ChAc) is caused by loss-of-function-mutations of the chorein-encoding gene VPS13A. In ChAc neurons transcript levels and protein abundance of Ca2+ release activated channel moiety (CRAC) Orai1 as well as its regulator STIM1/2 are decreased, resulting in blunted store operated Ca2+-entry (SOCE) and enhanced suicidal cell death. SOCE is up-regulated and cell death decreased by lithium. The effects of lithium are paralleled by upregulation of serum & glucocorticoid inducible kinase SGK1 and abrogated by pharmacological SGK1 inhibition. In other cell types SGK1 has been shown to be partially effective by upregulation of NFκB, a transcription factor stimulating the expression of Orai1 and STIM. The present study explored whether pharmacological inhibition of NFκB interferes with Orai1/STIM1/2 expression and SOCE and their upregulation by lithium in ChAc neurons. METHODS: Cortical neurons were differentiated from induced pluripotent stem cells generated from fibroblasts of ChAc patients and healthy volunteers. Orai1 and STIM1 transcript levels and protein abundance were estimated from qRT-PCR and Western blotting, respectively, cytosolic Ca2+-activity ([Ca2+]i) from Fura-2-fluorescence, SOCE from increase of [Ca2+]i following Ca2+ re-addition after Ca2+-store depletion with sarco-endoplasmatic Ca2+-ATPase inhibitor thapsigargin (1µM), as well as CRAC current utilizing whole cell patch clamp recording. RESULTS: Orai1 and STIM1 transcript levels and protein abundance as well as SOCE and CRAC current were significantly enhanced by lithium treatment (2 mM, 24 hours). These effects were reversed by NFκB inhibitor wogonin (50 µM). CONCLUSION: The stimulation of expression and function of Orai1/STIM1/2 by lithium in ChAc neurons are disrupted by pharmacological NFκB inhibition.

Mouse model of chorea-acanthocytosis exhibits male infertility caused by impaired sperm motility as a result of ultrastructural morphological abnormalities in the mitochondrial sheath in the sperm midpiece.

Chorea-acanthocytosis (ChAc) is an autosomal recessive hereditary disease characterized by neurodegeneration in the striatum and acanthocytosis caused by loss-of-function mutations in the Vacuolar Protein Sorting 13 Homolog A (VPS13A) gene, which encodes chorein. We previously produced a ChAc-model mouse with a homozygous deletion of exons 60-61 in Vps13a, which corresponded to the human disease mutation. We found that male ChAc-model mice exhibited complete infertility as a result of severely diminished sperm motility. Immunocytochemical study revealed that chorein-like immunoreactivity is abundant only in the midpiece, mitochondria-rich region, of the sperm of wild type mice. They showed no significant differences from wild types in terms of the adenosine 5'-triphosphate (ATP) concentration of their sperm, sperm count, or sexual activity. Electron microscopy revealed abnormal ultrastructural morphology of the mitochondria in the midpiece of sperm from ChAc-model mice. These results suggest that chorein is essential in mouse sperm for the maintenance of ultrastructural mitochondrial morphology and sperm motility.

Seizures as presenting and prominent symptom in chorea-acanthocytosis with c.2343del VPS13A gene mutation.

OBJECTIVE: The aim of the study was to characterize the clinical features of nine patients in three families with chorea-acanthocytosis (ChAc) sharing the same rare c.2343del mutation in the VPS13A gene. METHODS: Genetic test results, clinical description, magnetic resonance imaging (MRI), and electroencephalography (EEG), as well as laboratory results are summarized. RESULTS: ChAc is a rare genetic disorder characterized by hyperkinetic movements, seizures, cognitive decline, neuropsychiatric symptoms, and acanthocytes on peripheral blood smear. This unique cohort of nine patients is characterized by seizures as a first and prominent symptom. In our patients, other features of ChAc appeared later, including tics, other movement disorders, dysarthria, and mild to moderate cognitive decline. SIGNIFICANCE: Patients with chorea-acanthocytosis carrying the described rare mutation can present with focal, treatment-resistant seizures.

The Role of Chorein Deficiency in Late Spermatogenesis.

VPS13A, also known as chorein, whose loss of function causes chorea-acanthocytosis (ChAc), is characterized by Huntington's-disease-like neurodegeneration and neuropsychiatric symptoms in addition to acanthocytosis in red blood cells. We previously reported that ChAc-model mice with a loss of chorein function exhibited male infertility, with asthenozoospermia and mitochondrial dysmorphology in the spermatozoa. Here, we report a novel aspect of chorein dysfunction in male fertility, particularly its role in spermatogenesis and mitochondrial integrity. An increase in anti-malondialdehyde antibody immunoreaction within the testes, predominantly observed at the advanced stages of sperm formation in chorein-deficient mice, suggests oxidative stress as a contributing factor to mitochondrial dysfunction and impaired sperm maturation. The chorein immunoreactivity in spermatids of wild-type mice accentuates its significance in sperm development. ChAc-model mice exhibit mitochondrial ultrastructural abnormalities, specifically during the late stages of sperm maturation, suggesting a critical timeframe for chorein's action in spermiogenesis. We observed an increase in TOM20 protein levels, indicative of disrupted mitochondrial import mechanisms. The concurrent decrease in metabolic enzymes such as IDH3A, LDHC, PGK2, and ACAT1 suggests a complex chorein-mediated metabolic network that is essential for sperm vitality. Additionally, heightened separation of cytoplasmic droplets from sperm highlights the potential membrane instability in chorein-deficient spermatozoa. Metabolomic profiling further suggests a compensatory metabolic shift, with elevated glycolytic and TCA-cycle substrates. Our findings suggest that chorein is involved in anti-ferroptosis and the maturation of mitochondrial morphology in the late stages of spermatogenesis, and its deficiency leads to asthenozoospermia characterized by membrane instability, abnormal cytosolic glycolysis, abnormal mitochondrial function, and a disrupted TCA cycle. Further analyses are required to unravel the molecular mechanisms that directly link these findings and to elucidate the role of chorein in spermatogenesis as well as its broader implications.

Chorein, the protein responsible for chorea-acanthocytosis, interacts with ß-adducin and ß-actin.

Chorea-acanthocytosis (ChAc) is an autosomal, recessive hereditary disease characterized by striatal neurodegeneration and acanthocytosis, and caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene. VPS13A encodes chorein whose physiological function at the molecular level is poorly understood. In this study, we show that chorein interacts with ß-adducin and ß-actin. We first compare protein expression in human erythrocyte membranes using proteomic analysis. Protein levels of ß-adducin isoform 1 and ß-actin are markedly decreased in erythrocyte membranes from a ChAc patient. Subsequent co-immunoprecipitation (co-IP) and reverse co-IP assays using extracts from chorein-overexpressing human embryonic kidney 293 (HEK293) cells, shows that ß-adducin (isoforms 1 and 2) and ß-actin interact with chorein. Immunocytochemical analysis using chorein-overexpressing HEK293 cells demonstrates co-localization of chorein with ß-adducin and ß-actin. In addition, immunoreactivity of ß-adducin isoform 1 is significantly decreased in the striatum of gene-targeted ChAc-model mice. Adducin and actin are membrane cytoskeletal proteins, involved in synaptic function. Expression of ß-adducin is restricted to the brain and hematopoietic tissues, corresponding to the main pathological lesions of ChAc, and thereby implicating ß-adducin and ß-actin in ChAc pathogenesis.

Chorein sensitive microtubule organization in tumor cells.

Background: The purpose of this study is to analyzed the involvement of chorein in microtubules organization of three types of malignant; rhabdomyosarcoma tumor cells (ZF), rhabdomyosarcoma cells (RH30), and rhabdomyosarcoma cells (RD). ZF are expressing high chorein levels. Previous studies revealed that chorein protein silencing in ZF tumor cells persuaded apoptotic response followed by cell death. In addition, in numerous malignant and non-malignant cells this protein regulates actin cytoskeleton structure and cellular signaling. However, the function of chorein protein in microtubular organization is yet to be established. Methods: In a current research study, we analyzed the involvement of chorein in microtubules organization by using three types of malignant rhabdomyosarcoma cells. We have applied confocal laser-scanning microscopy to analyze microtubules structure and RT-PCR to examine cytoskeletal gene transcription. Results: We report here that in rhabdomyosarcoma cells (RH30), chorein silencing induced disarrangement of microtubular network. This was documented by laser scanning microscopy and further quantified by FACS analysis. Interestingly and in agreement with previous reports, tubulin gene transcription in RH cells was unchanged upon silencing of chorein protein. Equally, confocal analysis showed minor disordered microtubules organization with evidently weakened staining in rhabdomyosarcoma cells (RD and ZF) after silencing of chorein protein. Conclusion: These results disclose that chorein silencing induces considerable structural disorganization of tubulin network in RH30 human rhabdomyosarcoma tumor cells. Additional studies are now needed to establish the role of chorein in regulating cytoskeleton architecture in tumor cells.

ATG2 and VPS13 proteins: molecular highways transporting lipids to drive membrane expansion and organelle communication.

Communication between organelles is an essential process that helps maintain cellular homeostasis and organelle contact sites have recently emerged as crucial mediators of this communication. The emergence of a class of molecular bridges that span the inter-organelle gaps has now been shown to direct the flow of lipid traffic from one lipid bilayer to another. One of the key components of these molecular bridges is the presence of an N-terminal Chorein/VPS13 domain. This is an evolutionarily conserved domain present in multiple proteins within the endocytic and autophagy trafficking pathways. Herein, we discuss the current state-of-the-art of this class of proteins, focusing on the role of these lipid transporters in the autophagy and endocytic pathways. We discuss the recent biochemical and structural advances that have highlighted the essential role Chorein-N domain containing ATG2 proteins play in driving the formation of the autophagosome and how lipids are transported from the endoplasmic reticulum to the growing phagophore. We also consider the VPS13 proteins, their role in organelle contacts and the endocytic pathway and highlight how disease-causing mutations disrupt these contact sites. Finally, we open the door to discuss other Chorein_N domain containing proteins, for instance, UHRF1BP1/1L, their role in disease and look towards prokaryote examples of Chorein_N-like domains. Taken together, recent advances have highlighted an exciting opportunity to delve deeper into inter-organelle communication and understand how lipids are transported between membrane bilayers and how this process is disrupted in multiple diseases.

Csf1: A Putative Lipid Transport Protein Required for Homeoviscous Adaptation of the Lipidome.

The non-vesicular transport of lipids between organelles mediated by lipid transport proteins (LTPs) is a key determinant of organelle biogenesis and function. Despite performing a vital function in organelle homeostasis, none of the LTP-encoding genes identified so far are truly essential, even in the simple genome of yeast, suggesting widespread redundancy. In line with this fact, it has been found that a number of LTPs have overlapping functions, making it challenging to assign unique roles for an individual LTP in lipid distribution. In our genetic screens under stringent conditions in which the distinct function of an LTP might become essential, we stumbled upon Csf1, a highly conserved protein with a Chorein-N motif found in other lipid transporters and unraveled a new function for Csf1 in lipid remodeling and homeoviscous adaptation of the lipidome. Here, we further speculate on the potential mechanisms of how the putative function of Csf1 in lipid transport could be intimately connected to its role in lipid remodeling across organelles.

Insights into VPS13 properties and function reveal a new mechanism of eukaryotic lipid transport.

The occurrence of protein mediated lipid transfer between intracellular membranes has been known since the late 1960's. Since these early discoveries, numerous proteins responsible for such transport, which often act at membrane contact sites, have been identified. Typically, they comprise a lipid harboring module thought to shuttle back and forth between the two adjacent bilayers. Recently, however, studies of the chorein domain protein family, which includes VPS13 and ATG2, has led to the identification of a novel mechanism of lipid transport between organelles in eukaryotic cells mediated by a rod-like protein bridge with a hydrophobic groove through which lipids can slide. This mechanism is ideally suited for bulk transport of bilayer lipids to promote membrane growth. Here we describe how studies of VPS13 led to the discovery of this new mechanism, summarize properties and known roles of VPS13 proteins, and discuss how their dysfunction may lead to disease.

Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis.

Chorea-Acanthocytosis (ChAc) is a devastating, little understood, and currently untreatable neurodegenerative disease caused by VPS13A mutations. Based on our recent demonstration that accumulation of activated Lyn tyrosine kinase is a key pathophysiological event in human ChAc cells, we took advantage of Vps13a-/- mice, which phenocopied human ChAc. Using proteomic approach, we found accumulation of active Lyn, γ-synuclein and phospho-tau proteins in Vps13a-/- basal ganglia secondary to impaired autophagy leading to neuroinflammation. Mice double knockout Vps13a-/- Lyn-/- showed normalization of red cell morphology and improvement of autophagy in basal ganglia. We then in vivo tested pharmacologic inhibitors of Lyn: dasatinib and nilotinib. Dasatinib failed to cross the mouse brain blood barrier (BBB), but the more specific Lyn kinase inhibitor nilotinib, crosses the BBB. Nilotinib ameliorates both Vps13a-/- hematological and neurological phenotypes, improving autophagy and preventing neuroinflammation. Our data support the proposal to repurpose nilotinib as new therapeutic option for ChAc patients.

Inter-organelle lipid transfer: a channel model for Vps13 and chorein-N motif proteins.

Membrane contact sites, where two organelles are in close proximity, are critical regulators of cellular membrane homeostasis, with roles in signaling, lipid metabolism, and ion dynamics. A growing catalog of specialized lipid transfer proteins carry out lipid exchange at these sites. Currently characterized eukaryotic lipid transport proteins are shuttles that typically extract a single lipid from the membrane of the donor organelle, solubilize it during transport through the cytosol, and deposit it in the acceptor organelle membrane. Here, we highlight the recently identified chorein_N family of lipid transporters, including the Vps13 proteins and the autophagy protein Atg2. These are elongated proteins that, distinct from previously characterized transport proteins, bind tens of lipids at once. They feature an extended channel, most likely lined with hydrophobic residues. We discuss the possibility that they are not shuttles but instead are bridges between membranes, with lipids traversing the cytosol via the hydrophobic channel.

Identification of two compound heterozygous VPS13A large deletions in chorea-acanthocytosis only by protein and quantitative DNA analysis.

BACKGROUND: Chorea-acanthocytosis (ChAc; OMIM #200150) is a rare autosomal recessive condition with onset in early adulthood that is caused by mutations in the vacuolar protein sorting 13A (VPS13A) gene encoding chorein. Several diagnostic genomic DNA (gDNA) sequencing approaches are widely used. However, their limitations appear not to be acknowledged thoroughly enough. METHODS: Clinically, we deployed magnetic resonance imaging, blood smear analysis, and clinical chemistry for the index patient's characterization. The molecular analysis of the index patient next to his parents covered genomic DNA (gDNA) sequencing approaches, RNA/cDNA sequencing, and chorein specific Western blot. RESULTS: We report a 33-year-old male patient without functional protein due to compound heterozygosity for two VPS13A large deletions of 1168 and 1823 base pairs (bp) affecting, respectively, exons 8 and 9, and exon 13. To our knowledge, this represents the first ChAc case with two compound heterozygous large deletions identified so far. Of note, standard genomic DNA (gDNA) Sanger sequencing approaches alone yielded false negative findings. CONCLUSION: Our case demonstrates the need to carry out detection of chorein in patients suspected of having ChAc as a helpful and potentially decisive tool to establish diagnosis. Furthermore, the course of the molecular analysis in this case discloses diagnostic pitfalls in detecting some variations, such as deletions, using only standard genomic DNA (gDNA) Sanger sequencing approaches and exemplifies alternative methods, such as RNA/cDNA sequencing or qRT-PCR analysis, necessary to avoid false negative results.

The binding of the APT1 domains to phosphoinositides is regulated by metal ions in vitro.

Chorein is a protein of the Vps13 family, and defects in this protein cause the rare neurodegenerative disorder chorea-acanthocytosis (ChAc). Chorein is involved in the actin cytoskeleton organization, calcium ion flux, neuronal cell excitability, exocytosis and autophagy. The function of this protein is poorly understood, and obtaining this knowledge is a key to finding a cure for ChAc. Chorein, as well as the Vps13 protein from yeast, contains the APT1 domain. Our previous research has shown that the APT1 domain from yeast Vps13 (yAPT1v) binds phosphatidylinositol 3-phosphate (PI3P) in vitro. In this study, we showed that although the APT1 domain from chorein (hAPT1) binds to PI3P it could not functionally replace yAPT1v. The hAPT1 domain binds, in addition to PI3P, to phosphatidylinositol 5-phosphate (PI5P). The binding of hAPT1 to PI3P, unlike the binding of yAPT1v to PI3P, is regulated by the bivalent ions, calcium and magnesium. Regulation of PI3P binding via calcium is also observed for the APT1 domain of yeast autophagy protein Atg2. The substitution I2771R, found in chorein of patient suffering from ChAc, reduces the binding of the hAPT1 domain to PI3P and PI5P. These results suggest that the ability of APT1 domains to bind phosphoinositides is regulated differently in yeast and human protein and that this regulation is important for chorein function.

VPS13A is closely associated with mitochondria and is required for efficient lysosomal degradation.

Members of the VPS13 family are associated with various human diseases. In particular, the loss of function of VPS13A leads to chorea-acanthocytosis (ChAc), a rare neurodegenerative disease without available curative treatments. Autophagy has been considered a promising therapeutic target because the absence of VPS13A causes a defective autophagy flux. However, the mechanistic details of this deficiency are unknown. Here, we identified Rab7A as an interactor of one of the VPS13 family members in Dictyostelium discoideum and showed that this interaction is conserved between the human homologs VPS13A and RAB7A in HeLa cells. As RAB7A is a key player in endosome trafficking, we addressed the possible function of VPS13A in endosome dynamics and lysosome degradation. Our results suggest that the decrease in autophagy observed in the absence of VPS13A may be the result of a more general defect in endocytic trafficking and lysosomal degradation. Unexpectedly, we found that VPS13A is closely localized to mitochondria, suggesting that the role of VPS13A in the endolysosomal pathway might be related to inter-organelle communication. We show that VPS13A localizes at the interface between mitochondria-endosomes and mitochondria-endoplasmic reticulum and that the presence of membrane contact sites is altered in the absence of VPS13A. Based on these findings, we propose that therapeutic strategies aimed at modulating the endolysosomal pathway could be beneficial in the treatment of ChAc.This article has an associated First Person interview with the first author of the paper.

Remote homology searches identify bacterial homologues of eukaryotic lipid transfer proteins, including Chorein-N domains in TamB and AsmA and Mdm31p.

BACKGROUND: All cells rely on lipids for key functions. Lipid transfer proteins allow lipids to exit the hydrophobic environment of bilayers, and cross aqueous spaces. One lipid transfer domain fold present in almost all eukaryotes is the TUbular LIPid binding (TULIP) domain. Three TULIP families have been identified in bacteria (P47, OrfX2 and YceB), but their homology to eukaryotic proteins is too low to specify a common origin. Another recently described eukaryotic lipid transfer domain in VPS13 and ATG2 is Chorein-N, which has no known bacterial homologues. There has been no systematic search for bacterial TULIPs or Chorein-N domains. RESULTS: Remote homology predictions for bacterial TULIP domains using HHsearch identified four new TULIP domains in three bacterial families. DUF4403 is a full length pseudo-dimeric TULIP with a 6 strand ß-meander dimer interface like eukaryotic TULIPs. A similar sheet is also present in YceB, suggesting it homo-dimerizes. TULIP domains were also found in DUF2140 and in the C-terminus DUF2993. Remote homology predictions for bacterial Chorein-N domains identified strong hits in the N-termini of AsmA and TamB in diderm bacteria, which are related to Mdm31p in eukaryotic mitochondria. The N-terminus of DUF2993 has a Chorein-N domain adjacent to its TULIP domain. CONCLUSIONS: TULIP lipid transfer domains are widespread in bacteria. Chorein-N domains are also found in bacteria, at the N-terminus of multiple proteins in the intermembrane space of diderms (AsmA, TamB and their relatives) and in Mdm31p, a protein that is likely to have evolved from an AsmA/TamB-like protein in the endosymbiotic mitochondrial ancestor. This indicates that both TULIP and Chorein-N lipid transfer domains may have originated in bacteria.

Current state of knowledge in Chorea-Acanthocytosis as core Neuroacanthocytosis syndrome.

Neuroacanthocytosis (NA) syndromes are a group of rare diseases characterized by neurological disorders and misshaped spiky red blood cells (acanthocytes) including Chorea-Acanthocytosis (ChAc), McLeod syndrome (MLS), Huntington disease-like 2 (HDL 2), pantothenate kinase-associated neurodegeneration (PKAN), abeta- and hypobetalipoproteinemia and aceruloplasminemia. This clinically and genetically heterogeneous group of diseases shares main clinical features presenting most often as a hyperkinetic movement disorder. Even though these are long noted disease conditions, we still know only little on the underlying disease mechanisms. The current review focuses upon ChAc as the core entity of NA syndromes caused by mutations in the VPS13A gene. The support of patient organizations and the ERA-NET initiative yielded to different multidisciplinary efforts with significant progress on our understanding of ChAc. Disturbances in two pathways are currently considered to be significantly involved in the pathophysiology of ChAc, namely elevated Lyn kinase phosphorylation and decreased signaling via Phosphoinositide 3-kinase (PI3K). These recent developments may reveal potential drugable targets for causative therapies of ChAc.