TY  - GEN
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
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.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 232 
KW  - cells
KW  - coenzyme-a
KW  - database
KW  - energy-metabolism
KW  - glutathione
KW  - hallervorden-spatz-syndrome
KW  - mobility-mass spectrometry
KW  - model
KW  - neurodegeneration
KW  - neurotoxicity
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-94314
SP  - 363
EP  - 370
ER  - 
TY  - CHAP
A1  - Tidball, Andrew M.
A1  - Kumar, Kevin K.
A1  - Bryan, Miles R.
A1  - Bichell, Terry Jo
A1  - Horning, Kyle
A1  - Uhouse, Michael A.
A1  - Goodwin, Cody R.
A1  - Bornhorst, Julia
A1  - Schwerdtle, Tanja
A1  - Neely, Maja Diana
A1  - McClean, John A.
A1  - Aschner, Michael A.
A1  - Bowman, Aaron B.
T1  - Deficits in neural responses to manganese exposure in Huntington's disease models
T2  - Neurotoxicology and teratology
Y1  - 2015
U6  - https://doi.org/10.1016/j.ntt.2015.04.022
SN  - 0892-0362
SN  - 1872-9738
VL  - 49
SP  - 105
EP  - 105
PB  - Elsevier
CY  - Oxford
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
JF  - Metallomics : integrated biometal science
Y1  - 2015
U6  - https://doi.org/10.1039/c4mt00223g
SN  - 1756-5901
SN  - 1756-591X
VL  - 7
IS  - 2
SP  - 363
EP  - 370
PB  - Royal Society of Chemistry
CY  - Cambridge
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  -