Exacerbation of sensorimotor dysfunction in mice deficient in Atp13a2 and overexpressing human wildtype alpha-synuclein.
*Alpha-synuclein; *ATP13A2; *Mice; *Phenotype; *Sensorimotor; Adenosine Triphosphatases/*deficiency/genetics; alpha-Synuclein/genetics/*metabolism; Animal; Animals; Body Temperature; Body Weight; Disease Models; Female; Gait Disorders; Humans; Inbred C57BL; Male; Membrane Proteins/*deficiency/genetics; Mice; Motor Skills/physiology; Neurologic/*metabolism; Phenotype; Severity of Illness Index; Sex Characteristics; Transgenic
Loss of function mutations in the gene ATP13A2 are associated with Kufor-Rakeb Syndrome and Neuronal Ceroid Lipofuscinosis, the former designated as an inherited form of Parkinson's disease (PD). The function of ATP13A2 is unclear but in vitro studies indicate it is a lysosomal protein and may interact with the presynaptic protein alpha-synuclein (aSyn) and certain heavy metals. Accumulation of aSyn is a major component of lewy bodies, the pathological hallmark of PD. Atp13a2-deficient (13a2) mice develop age-dependent sensorimotor deficits, and accumulation of insoluble aSyn in the brain. To better understand the interaction between ATP13A2 and aSyn, double mutant mice with loss of Atp13a2 function combined with overexpression of human wildtype aSyn were generated. Female and male wildtype (WT), 13a2, aSyn, and 13a2-aSyn mice were tested on a battery of sensorimotor tests including adhesive removal, challenging beam traversal, spontaneous activity, gait, locomotor activity, and nest-building at 2, 4, and 6 months of age. Double mutant mice showed an earlier onset and accelerated alterations in sensorimotor function that were age, sex and test-dependent. Female 13a2-aSyn mice showed early and progressive dysfunction on the beam and in locomotor activity. In males, 13a2-aSyn mice showed more severe impairments in spontaneous activity and adhesive removal. Sex differences were also observed in aSyn and 13a2-aSyn mice on the beam, cylinder, and adhesive removal tests. In other tasks, double mutant mice displayed deficits similar to aSyn mice. These results indicate loss of Atp13a2 function exacerbates the sensorimotor phenotype in aSyn mice in an age and sex-dependent manner.
Dirr Emily R; Ekhator Osunde R; Blackwood Rachel; Holden John G; Masliah Eliezer; Schultheis Patrick J; Fleming Sheila M
Behavioural brain research
2018
2018-05
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.bbr.2018.01.029" target="_blank" rel="noreferrer noopener">10.1016/j.bbr.2018.01.029</a>
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>