TY  - JOUR
A1  - Henze, Andrea
A1  - Homann, Thomas
A1  - Rohn, Isabelle
A1  - Aschner, Michael A.
A1  - Link, Christopher D.
A1  - Kleuser, Burkhard
A1  - Schweigert, Florian J.
A1  - Schwerdtle, Tanja
A1  - Bornhorst, Julia
T1  - Caenorhabditis elegans as a model system to study post-translational modifications of human transthyretin
JF  - Scientific reports
N2  - The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time- and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization – time of flight – mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling.
KW  - n-acetyl-cysteine
KW  - s-glutathionylation
KW  - force-field
KW  - c. elegans
KW  - life-span
KW  - protein
KW  - cells
KW  - menadione
KW  - disease
KW  - binding
Y1  - 2016
U6  - https://doi.org/10.1038/srep37346
SN  - 2045-2322
VL  - 6
PB  - Nature Publishing Group
CY  - London
ER  - 
TY  - JOUR
A1  - Kumar, Kevin K.
A1  - Goodwin, Cody R.
A1  - Uhouse, Michael A.
A1  - Bornhorst, Julia
A1  - Schwerdtle, Tanja
A1  - Aschner, Michael A.
A1  - McLean, John A.
A1  - Bowman, Aaron B.
T1  - Untargeted metabolic profiling identifies interactions between Huntington's disease and neuronal manganese status
JF  - Metallomics
N2  - Manganese (Mn) is an essential micronutrient for development and function of the nervous system. Deficiencies in Mn transport have been implicated in the pathogenesis of Huntington's disease (HD), an autosomal dominant neurodegenerative disorder characterized by loss of medium spiny neurons of the striatum. Brain Mn levels are highest in striatum and other basal ganglia structures, the most sensitive brain regions to Mn neurotoxicity. Mouse models of HD exhibit decreased striatal Mn accumulation and HD striatal neuron models are resistant to Mn cytotoxicity. We hypothesized that the observed modulation of Mn cellular transport is associated with compensatory metabolic responses to HD pathology. Here we use an untargeted metabolomics approach by performing ultraperformance liquid chromatography-ion mobility-mass spectrometry (UPLC-IM-MS) on control and HD immortalized mouse striatal neurons to identify metabolic disruptions under three Mn exposure conditions, low (vehicle), moderate (non-cytotoxic) and high (cytotoxic). Our analysis revealed lower metabolite levels of pantothenic acid, and glutathione (GSH) in HD striatal cells relative to control cells. HD striatal cells also exhibited lower abundance and impaired induction of isobutyryl carnitine in response to increasing Mn exposure. In addition, we observed induction of metabolites in the pentose shunt pathway in HD striatal cells after high Mn exposure. These findings provide metabolic evidence of an interaction between the HD genotype and biologically relevant levels of Mn in a striatal cell model with known HD by Mn exposure interactions. The metabolic phenotypes detected support existing hypotheses that changes in energetic processes underlie the pathobiology of both HD and Mn neurotoxicity.
KW  - hallervorden-spatz-syndrome
KW  - mobility-mass spectrometry
KW  - energy-metabolism
KW  - coenzyme-a
KW  - model
KW  - neurotoxicity
KW  - glutathione
KW  - database
KW  - cells
KW  - neurodegeneration
Y1  - 2015
U6  - https://doi.org/10.1039/C4MT00223G
SN  - 1756-591X
SN  - 1756-5901
VL  - 7
SP  - 363
EP  - 370
PB  - RSC Publ.
CY  - Cambridge
ER  -