RESUMEN
Huntington's disease (HD) is caused by a mutation in the huntingtin gene (HTT), resulting in profound striatal neurodegeneration through an unknown mechanism. Perturbations in the urea cycle have been reported in HD models and in HD patient blood and brain. In neurons, arginase is a central urea cycle enzyme, and the metal manganese (Mn) is an essential cofactor. Deficient biological responses to Mn, and reduced Mn accumulation have been observed in HD striatal mouse and cell models. Here we report in vivo and ex vivo evidence of a urea cycle metabolic phenotype in a prodromal HD mouse model. Further, either in vivo or in vitro Mn supplementation reverses the urea-cycle pathology by restoring arginase activity. We show that Arginase 2 (ARG2) is the arginase enzyme present in these mouse brain models, with ARG2 protein levels directly increased by Mn exposure. ARG2 protein is not reduced in the prodromal stage, though enzyme activity is reduced, indicating that altered Mn bioavailability as a cofactor leads to the deficient enzymatic activity. These data support a hypothesis that mutant HTT leads to a selective deficiency of neuronal Mn at an early disease stage, contributing to HD striatal urea-cycle pathophysiology through an effect on arginase activity.
Asunto(s)
Cuerpo Estriado/metabolismo , Enfermedad de Huntington/metabolismo , Manganeso/metabolismo , Neuronas/metabolismo , Urea/metabolismo , Animales , Arginasa/metabolismo , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Enfermedad de Huntington/patología , Masculino , Ratones , Neuronas/patologíaRESUMEN
Introduction: SLC6A1 Neurodevelopmental Disorder (SLC6A1-NDD), first described in 2015, is a rare syndrome caused by a mutation in the SLC6A1 gene which encodes for the GABA Transporter 1 (GAT-1) protein. Epilepsy is one of the most common symptoms in patients and is often the primary treatment target, though the severity of epilepsy is variable. The impact of seizures and other symptoms of SLC6A1-NDD on patients and caregivers is wide-ranging and has not been described in a formal disease concept study. Methods: A literature search was performed using the simple search term, "SLC6A1." Papers published before 2015, and those which did not describe the human neurodevelopmental disorder were removed from analysis. Open-ended interviews on lived experiences were conducted with two patient advocate key opinion leaders. An analysis of de-identified conversations between families of people with SLC6A1-NDD on social media was performed to quantify topics of concern. Results: Published literature described symptoms in all of the following domains: neurological, visual, motor, cognitive, communication, behavior, gastrointestinal, sleep, musculo-skeletal, and emotional in addition to epilepsy. Key opinion leaders noted two unpublished features: altered hand use in infants, and developmental regression with onset of epilepsy. Analysis of social media interactions confirmed that the core symptoms of epilepsy and autistic traits were prominent concerns, but also demonstrated that other symptoms have a large impact on family life. Discussion: For rare diseases, analysis of published literature is important, but may not be as comprehensive as that which can be gleaned from spontaneous interactions between families and through qualitative interviews. This report reflects our current understanding of the lived experience of SLC6A1-NDD. The discrepancy between the domains of disease reported in the literature and those discussed in patient conversations suggests that a formal qualitative interview-based disease concept study of SLC6A1-NDD is warranted.