32 research outputs found
Metabolic alterations in Charcot-Marie-Tooth disease type 1A
No full textAxo-glia interaction extend beyond myelination itself. Glial cells support axons with metabolites and trophic factors. In numerous disease models, primary glial mutations result in the disturbance of normal nerve conduction. In Charcot-Marie-Tooth disease type 1A (CMT1A), an overexpression of peripheral myelin protein 22 (PMP22) in Schwann cells (SC), the myelinating glial cells of the peripheral nervous system, results in severely reduced nerve conduction velocities and eventually loss of compound muscle action potentials (CMAP) in patients as well as in a rat model (Pmp22tg). Previous studies have reported that reduced axonal numbers and alterations in mRNA expression of the metabolic machinery correlate with disease severity. Recent evidence implicating failed metabolic support in other models of peripheral neuropathies highlight its importance for functional axo-glial interaction. Here, we hypothesize that in CMT1A the challenged SC is no longer able to metabolically support axonal function. In a metabolomics approach complemented with qRT-PCR analysis in nerve lysates of Pmp22tg animals alterations in glucose metabolism were observed. Interestingly, free glucose was enriched while a downregulation of the polyol pathway was observed and no increase of glycogen storages or glycolysis machinery was detected. Glucose transporter1 was increased and localized to Schmidt-Lanterman Incisures as well as the ab- and adaxonal SC surface possibly allowing for the shuttling of free glucose to the axon. We hypothesize that free glucose concentrations fuel the axonal metabolism in peripheral nerves of Pmp22tg animals. Mitochondria of diseased axons showed morphological alterations and adenosine triphosphate (ATP) levels of axons in old Pmp22tg animals decreased as compared to wild type animals. The expression of the mitochondrial gene COX6C detected in blood of CMT1A patients correlated with handgrip strength underlining the importance of mitochondrial alterations in disease pathogenesis. Our data suggest that free glucose is not primarily metabolized in SC, but instead is transported to the axons to meet metabolic demands. During the course of the disease, the increased supply becomes deleterious as a potential axonal glucose overload might drive axonal loss, neuromuscular junction degeneration and muscle atrophy. Understanding the details of axo-glial metabolic coupling in health and its alteration in diseases may promote novel therapeutic targets.2022-03-2
Hyperactivity is a Core Endophenotype of Elevated Neuregulin-1 Signaling in Embryonic Glutamatergic Networks
No full textAbstract The neuregulin 1 (NRG1) ErbB4 module is at the core of an “at risk” signaling pathway in schizophrenia. Several human studies suggest hyperstimulation of NRG1-ErbB4 signaling as a plausible pathomechanism; however, little is known about the significance of stage-, brain area-, or neural cell type-specific NRG1-ErbB4 hyperactivity for disease-relevant brain endophenotypes. To address these spatiotemporal aspects, we generated transgenic mice for Cre recombinase-mediated overexpression of cystein-rich domain (CRD) NRG1, the most prominent NRG1 isoform in the brain. A comparison of “brain-wide” vs cell type-specific CRD-NRG1 overexpressing mice revealed that pathogenic CRD-NRG1 signals for ventricular enlargement and neuroinflammation originate outside glutamatergic neurons and suggests a subcortical function of CRD-NRG1 in the control of body weight. Embryonic onset of CRD-NRG1 in glutamatergic cortical networks resulted in reduced inhibitory neurotransmission and locomotor hyperactivity. Our findings identify ventricular enlargement and locomotor hyperactivity, 2 main endophenotypes of schizophrenia, as specific consequences of spatiotemporally distinct expression profiles of hyperactivated CRD-NRG1 signaling
Author Correction: The NLR gene family: from discovery to present day
No full textAuthor Correction: The NLR gene family: from discovery to present da
Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot–Marie–Tooth disease type 1A (CMT1A) rats
No full textSurvey report 1999/2000 summer season Voyage 4 to 6 Australian Antarctic Division Author - Mark Anderson / UTAS
No full textProgress Code: completedStatement: The values provided in spatial coverage are estimates only.
See the report for further information.Taken from sections of the Report:<br/><br/>The main purpose of the 1999-2000 Antarctic MAGIP Field Program was to provide survey support to a number of operations being undertaken around the Davis area.<br/><br/>These include aerial photography of the penguin rookeries, Tide Gauge work, GPS control of benchmarks in the Vestfold Hills and other associated levelling projects.<br/><br/>Myself, Mark Anderson, from the Centre for Spatial Information Science, University of Tasmania, was appointed as Surveyor for the 1999/00 season. I was to work in conjunction with Technical Consultant Roger Handsworth on various projects at Davis Station.<br/><br/>PROJECT OUTLINE<br/><br/>The 1999-2000 MAGIP Field Program Surveyor's Brief outlines the work to be undertaken during the period from V4 to V6 and is included in the Appendix of this report.<br/><br/>This year the Surveyor's program consisted of the following major projects:<br/><br/>- Aerial Photography of penguin rookeries<br/><br/>- This includes the aerial photography of the penguin colonies using the Linhoff camera. These penguin colonies are located on the Islands in the Davis station area.<br/><br/>- Antarctic Tide Gauge Network<br/><br/>- To locate the already installed mount for the new tide gauge using current markers and a new camera device, and then to deploy the new tide gauge in to this mooring.<br/>- Download data from existing tide gauges in the Davis area<br/>- Level run from AUS184 to the ARGN site.<br/>- Level run from AUS184 and AUS186 to HBM1 and HBM2 along specified routes as requested in brief.<br/><br/>- Location of benchmarks in the Vestfold Hills using GPS<br/><br/>- The listing of those benchmarks already controlled in previous seasons can be found in Matt King et al's report from last season. <br/>- This year it is envisaged to survey benchmarks in the outer areas of the Vestfold Hills as a priority.<br/>- Photographs of all benchmarks showing the general area of their location is to be taken.<br/>- Confirmation of the description of benchmarks in the Vestfold Hills area.<br/><br/>- Locate all new services and buildings in the station area and remove from maps all those buildings and services that no longer exist.<br/><br/>- Repair of 'tide pole' at Deep Lake.<br/><br/>Survey specifications, details to be included in the report and other such information can be found in the 1999-2000 brief to Surveyor's included in Appendix A of this report.<br/><br/>The Related URLs include links to where the following can be downloaded: <br/>1 The survey report; <br/>2 GIS data representing features at Davis and Macquarie Island station. Data resulting from this survey has Dataset_id = 35 in the attribute table.<br/>Features surveyed are listed in the report
