Dual Role of Ribosome-Binding Domain of NAC as a Potent Suppressor of Protein Aggregation and Aging-Related Proteinopathies

The nascent polypeptide-associated complex (NAC) is a conserved ribosome-associated protein biogenesis factor. Whether NAC exerts chaperone activity and whether this function is restricted to de novo protein synthesis is unknown. Here, we demonstrate that NAC directly exerts chaperone activity toward structurally diverse model substrates including polyglutamine (PolyQ) proteins, firefly luciferase, and Aβ40. Strikingly, we identified the positively charged ribosome-binding domain in the N terminus of the βNAC subunit (N-βNAC) as a major chaperone entity of NAC. N-βNAC by itself suppressed aggregation of PolyQ-expanded proteins in vitro, and the positive charge of this domain was critical for this activity. Moreover, we found that NAC also exerts a ribosome-independent chaperone function in vivo. Consistently, we found that a substantial fraction of NAC is non-ribosomal bound in higher eukaryotes. In sum, NAC is a potent suppressor of aggregation and proteotoxicity of mutant PolyQ-expanded proteins associated with human diseases like Huntington’s disease and spinocerebellar ataxias

Genome-Wide Association Study Identifies Genetic Loci Associated with Iron Deficiency

The existence of multiple inherited disorders of iron metabolism in man, rodents and other vertebrates suggests genetic contributions to iron deficiency. To identify new genomic locations associated with iron deficiency, a genome-wide association study (GWAS) was performed using DNA collected from white men aged ≥25 y and women ≥50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study with serum ferritin (SF) ≤ 12 µg/L (cases) and iron replete controls (SF>100 µg/L in men, SF>50 µg/L in women). Regression analysis was used to examine the association between case-control status (336 cases, 343 controls) and quantitative serum iron measures and 331,060 single nucleotide polymorphism (SNP) genotypes, with replication analyses performed in a sample of 71 cases and 161 controls from a population of white male and female veterans screened at a US Veterans Affairs (VA) medical center. Five SNPs identified in the GWAS met genome-wide statistical significance for association with at least one iron measure, rs2698530 on chr. 2p14; rs3811647 on chr. 3q22, a known SNP in the transferrin (TF) gene region; rs1800562 on chr. 6p22, the C282Y mutation in the HFE gene; rs7787204 on chr. 7p21; and rs987710 on chr. 22q11 (GWAS observed P<1.51×10−7 for all). An association between total iron binding capacity and SNP rs3811647 in the TF gene (GWAS observed P = 7.0×10−9, corrected P = 0.012) was replicated within the VA samples (observed P = 0.012). Associations with the C282Y mutation in the HFE gene also were replicated. The joint analysis of the HEIRS and VA samples revealed strong associations between rs2698530 on chr. 2p14 and iron status outcomes. These results confirm a previously-described TF polymorphism and implicate one potential new locus as a target for gene identification

Monte-Carlo-Simulation zur Elektron-Deuteron-Streuung

SIGLECopy held by FIZ Karlsruhe; available from UB/TIB Hannover / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

10 patients, 10 years - Long term follow-up of cardiovascular risk factors in Glut1 deficiency treated with ketogenic diet therapies: A&nbsp;prospective, multicenter case series.

Background and aims: Glut1 Deficiency (Glut1D) is caused by impaired glucose transport into brain. The resulting epileptic encephalopathy and movement disorders can be treated effectively by high-fat carbohydrate-restricted ketogenic diet therapies (KDT) mimicking fasting and providing ketones as an alternative cerebral fuel. Recently 6-24 months follow-ups of epileptic patients reported elevated blood lipids and intima thickening of the carotid artery raising concerns about potential cardiovascular risks by KDT. To clarify potential cardiovascular risks we performed a prospective 10 year follow up of 10 Glut1D patients.Methods: Between August 2001 and January 2016 we enrolled Glut1D patients on KDT at two hospitals in Germany in this prospective, multicenter case series. The minimal follow up was 10 years. Standard deviation scores (SDS) of body mass index (BMI), total cholesterol (TC), HDL-/LDL cholesterol, and triglycerides (TG) before initiation of KDT were compared with respective values at 6 months, 2, 5 years, and 10 years after initiation. After 10 years on KDT cardiovascular risk, assessed by BMI, carotid intima-media thickness (CIMT) measurement, and blood pressure, was compared to a healthy reference population (n = 550).Results: Baseline and 10 year follow-up investigations were available for 10 individuals with Glut1D on KDT. After two years on KDT BMI increased significantly, while total cholesterol, HDL-cholesterol, and LDL-cholesterol decreased. Within 3-5 years on KDT these differences disappeared, and after 10 years blood lipid parameters reflected the situation at initiation of KDT. Prior to KDT one child had dyslipidaemia, but no child after 10 years on KDT. No significant differences were observed with respect to BMI SDS (p = 0.26), CIMT (p = 0.63) or systolic and diastolic blood pressure (SDS p = 0.11 and p = 037, respectively) in Glut1D children treated with KDT for at least 10 years compared to healthy controls.Conclusions: In contrast to previous short-term reports on adverse effects of KDT, 10-year follow-up did not identify cardiovascular risks of dietary treatment for Glut1D. (C) 2017 The Authors. Published by Elsevier Ltd

Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group

Glut1 deficiency syndrome (Glut1DS) is a brain energy failure syndrome caused by impaired glucose transport across brain tissue barriers. Glucose diffusion across tissue barriers is facilitated by a family of proteins including glucose transporter type 1 (Glut1). Patients are treated effectively with ketogenic diet therapies (KDT) that provide a supplemental fuel, namely ketone bodies, for brain energy metabolism. The increasing complexity of Glut1DS, since its original description in 1991, now demands an international consensus statement regarding diagnosis and treatment. International experts (n = 23) developed a consensus statement utilizing their collective professional experience, responses to a standardized questionnaire, and serial discussions of wide-ranging issues related to Glut1DS. Key clinical features signaling the onset of Glut1DS are eye-head movement abnormalities, seizures, neurodevelopmental impairment, deceleration of head growth, and movement disorders. Diagnosis is confirmed by the presence of these clinical signs, hypoglycorrhachia documented by lumbar puncture, and genetic analysis showing pathogenic SLC2A1 variants. KDT represent standard choices with Glut1DS-specific recommendations regarding duration, composition, and management. Ongoing research has identified future interventions to restore Glut1 protein content and function. Clinical manifestations are influenced by patient age, genetic complexity, and novel therapeutic interventions. All clinical phenotypes will benefit from a better understanding of Glut1DS natural history throughout the life cycle and from improved guidelines facilitating early diagnosis and prompt treatment. Often, the presenting seizures are treated initially with antiseizure drugs before the cause of the epilepsy is ascertained and appropriate KDT are initiated. Initial drug treatment fails to treat the underlying metabolic disturbance during early brain development, contributing to the long-term disease burden. Impaired development of the brain microvasculature is one such complication of delayed Glut1DS treatment in the postnatal period. This international consensus statement should facilitate prompt diagnosis and guide best standard of care for Glut1DS throughout the life cycle. © 2020 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy

Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group

Glut1 deficiency syndrome (Glut1DS) is a brain energy failure syndrome caused by impaired glucose transport across brain tissue barriers. Glucose diffusion across tissue barriers is facilitated by a family of proteins including glucose transporter type 1 (Glut1). Patients are treated effectively with ketogenic diet therapies (KDT) that provide a supplemental fuel, namely ketone bodies, for brain energy metabolism. The increasing complexity of Glut1DS, since its original description in 1991, now demands an international consensus statement regarding diagnosis and treatment. International experts (n = 23) developed a consensus statement utilizing their collective professional experience, responses to a standardized questionnaire, and serial discussions of wide-ranging issues related to Glut1DS. Key clinical features signaling the onset of Glut1DS are eye-head movement abnormalities, seizures, neurodevelopmental impairment, deceleration of head growth, and movement disorders. Diagnosis is confirmed by the presence of these clinical signs, hypoglycorrhachia documented by lumbar puncture, and genetic analysis showing pathogenic SLC2A1 variants. KDT represent standard choices with Glut1DS-specific recommendations regarding duration, composition, and management. Ongoing research has identified future interventions to restore Glut1 protein content and function. Clinical manifestations are influenced by patient age, genetic complexity, and novel therapeutic interventions. All clinical phenotypes will benefit from a better understanding of Glut1DS natural history throughout the life cycle and from improved guidelines facilitating early diagnosis and prompt treatment. Often, the presenting seizures are treated initially with antiseizure drugs before the cause of the epilepsy is ascertained and appropriate KDT are initiated. Initial drug treatment fails to treat the underlying metabolic disturbance during early brain development, contributing to the long-term disease burden. Impaired development of the brain microvasculature is one such complication of delayed Glut1DS treatment in the postnatal period. This international consensus statement should facilitate prompt diagnosis and guide best standard of care for Glut1DS throughout the life cycle

Glut1 Deficiency Syndrome (Glut1DS ) : State of the art in 2020 and recommendations of the international Glut1DS study group

Glut1 deficiency syndrome (Glut1DS) is a brain energy failure syndrome caused by impaired glucose transport across brain tissue barriers. Glucose diffusion across tissue barriers is facilitated by a family of proteins including glucose transporter type 1 (Glut1). Patients are treated effectively with ketogenic diet therapies (KDT) that provide a supplemental fuel, namely ketone bodies, for brain energy metabolism. The increasing complexity of Glut1DS, since its original description in 1991, now demands an international consensus statement regarding diagnosis and treatment. International experts (n&nbsp;=&nbsp;23) developed a consensus statement utilizing their collective professional experience, responses to a standardized questionnaire, and serial discussions of wide-ranging issues related to Glut1DS. Key clinical features signaling the onset of Glut1DS are eye-head movement abnormalities, seizures, neurodevelopmental impairment, deceleration of head growth, and movement disorders. Diagnosis is confirmed by the presence of these clinical signs, hypoglycorrhachia documented by lumbar puncture, and genetic analysis showing pathogenic SLC2A1 variants. KDT represent standard choices with Glut1DS-specific recommendations regarding duration, composition, and management. Ongoing research has identified future interventions to restore Glut1 protein content and function. Clinical manifestations are influenced by patient age, genetic complexity, and novel therapeutic interventions. All clinical phenotypes will benefit from a better understanding of Glut1DS natural history throughout the life cycle and from improved guidelines facilitating early diagnosis and prompt treatment. Often, the presenting seizures are treated initially with antiseizure drugs before the cause of the epilepsy is ascertained and appropriate KDT are initiated. Initial drug treatment fails to treat the underlying metabolic disturbance during early brain development, contributing to the long-term disease burden. Impaired development of the brain microvasculature is one such complication of delayed Glut1DS treatment in the postnatal period. This international consensus statement should facilitate prompt diagnosis and guide best standard of care for Glut1DS throughout the life cycle