The effect of manganese exposure in Atp13a2-deficient mice.
*Alpha-synuclein; *Lipofuscin; *Manganese; *Mice; *Parkinson's disease; *Sensorimotor function
Loss of function mutations in the P5-ATPase ATP13A2 are associated with Kufor-Rakeb Syndrome and Neuronal Ceroid Lipofuscinosis. While the function of ATP13A2 is unclear, in vitro studies suggest it is a lysosomal protein that interacts with the metals manganese (Mn) and zinc and the presynaptic protein alpha-synuclein. Loss of ATP13A2 function in mice causes sensorimotor deficits, enhanced autofluorescent storage material, and accumulation of alpha-synuclein. The present study sought to determine the effect of Mn administration on these same outcomes in ATP13A2-deficient mice. Wildtype and ATP13A2-deficient mice received saline or Mn at 5-9 or 12-19 months for 45days. Sensorimotor function was assessed starting at day 30. Autofluorescence was quantified in multiple brain regions and alpha-synuclein protein levels were determined in the ventral midbrain. Brain Mn, iron, zinc, and copper concentrations were measured in 5-9 month old mice. The results show Mn enhanced sensorimotor function, increased autofluorescence in the substantia nigra, and increased insoluble alpha-synuclein in the ventral midbrain in older ATP13A2-deficient mice. In addition, the Mn regimen used increased Mn concentration in the brain and levels were higher in Mn-treated mutants than controls. These results indicate loss of ATP13A2 function leads to increased sensitivity to Mn in vivo.
Fleming Sheila M; Santiago Nicholas A; Mullin Elizabeth J; Pamphile Shanta; Karkare Swagata; Lemkuhl Andrew; Ekhator Osunde R; Linn Stephen C; Holden John G; Aga Diana S; Roth Jerome A; Liou Benjamin; Sun Ying; Shull Gary E; Schultheis Patrick J
Neurotoxicology
2018
2018-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.neuro.2017.06.005" target="_blank" rel="noreferrer noopener">10.1016/j.neuro.2017.06.005</a>
The effect of manganese exposure in Atp13a2-deficient mice.
Female; Male; Animals; Mice; *Parkinson's disease; *Alpha-synuclein; Mice; Membrane Proteins/genetics/*metabolism; Motor Activity; *Lipofuscin; *Manganese; *Sensorimotor function; Behavior; Inbred C57BL; Animal; Knockout; Adenosine Triphosphatases/genetics/*metabolism; alpha-Synuclein/metabolism; Brain/*drug effects/*metabolism; Manganese/metabolism/*toxicity
Loss of function mutations in the P5-ATPase ATP13A2 are associated with Kufor-Rakeb Syndrome and Neuronal Ceroid Lipofuscinosis. While the function of ATP13A2 is unclear, in vitro studies suggest it is a lysosomal protein that interacts with the metals manganese (Mn) and zinc and the presynaptic protein alpha-synuclein. Loss of ATP13A2 function in mice causes sensorimotor deficits, enhanced autofluorescent storage material, and accumulation of alpha-synuclein. The present study sought to determine the effect of Mn administration on these same outcomes in ATP13A2-deficient mice. Wildtype and ATP13A2-deficient mice received saline or Mn at 5-9 or 12-19 months for 45days. Sensorimotor function was assessed starting at day 30. Autofluorescence was quantified in multiple brain regions and alpha-synuclein protein levels were determined in the ventral midbrain. Brain Mn, iron, zinc, and copper concentrations were measured in 5-9 month old mice. The results show Mn enhanced sensorimotor function, increased autofluorescence in the substantia nigra, and increased insoluble alpha-synuclein in the ventral midbrain in older ATP13A2-deficient mice. In addition, the Mn regimen used increased Mn concentration in the brain and levels were higher in Mn-treated mutants than controls. These results indicate loss of ATP13A2 function leads to increased sensitivity to Mn in vivo.
Fleming Sheila M; Santiago Nicholas A; Mullin Elizabeth J; Pamphile Shanta; Karkare Swagata; Lemkuhl Andrew; Ekhator Osunde R; Linn Stephen C; Holden John G; Aga Diana S; Roth Jerome A; Liou Benjamin; Sun Ying; Shull Gary E; Schultheis Patrick J
Neurotoxicology
2018
2018-01
<a href="http://doi.org/10.1016/j.neuro.2017.06.005" target="_blank" rel="noreferrer noopener">10.1016/j.neuro.2017.06.005</a>
Modulating ryanodine receptors with dantrolene attenuates neuronopathic phenotype in Gaucher disease mice.
Animal; Animals; Calcium Signaling/genetics; Dantrolene/*administration & dosage; Disease Models; Gaucher Disease/*drug therapy/genetics/physiopathology; Humans; Mice; Mitochondria/*drug effects/genetics/pathology; Neurons/drug effects/pathology; Neuroprotective Agents/administration & dosage; Ryanodine Receptor Calcium Release Channel/*genetics/metabolism
Neuronopathic Gaucher disease (nGD) manifests as severe neurological symptoms in patients with no effective treatment available. Ryanodine receptors (Ryrs) are a family of calcium release channels on intracellular stores. The goal of this study is to determine if Ryrs are potential targets for nGD treatment. A nGD cell model (CBE-N2a) was created by inhibiting acid beta-glucosidase (GCase) in N2a cells with conduritol B epoxide (CBE). Enhanced cytosolic calcium in CBE-N2a cells was blocked by either ryanodine or dantrolene, antagonists of Ryrs and by Genz-161, a glucosylceramide synthase inhibitor, suggesting substrate-mediated
Liou Benjamin; Peng Yanyan; Li Ronghua; Inskeep Venette; Zhang Wujuan; Quinn Brian; Dasgupta Nupur; Blackwood Rachel; Setchell Kenneth D R; Fleming Sheila; Grabowski Gregory A; Marshall John; Sun Ying
Human molecular genetics
2016
2016-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1093/hmg/ddw322" target="_blank" rel="noreferrer noopener">10.1093/hmg/ddw322</a>