Distribution of Na/K-ATPase Alpha 3 Isoform, a Sodium-Potassium P-Type Pump Associated With Rapid-Onset of Dystonia Parkinsonism (RDP) in the Adult Mouse Brain

The Na+/K+-ATPase1 alpha subunit 3 (ATP1 alpha(3)) is one of many essential components that maintain the sodium and potassium gradients across the plasma membrane in animal cells. Mutations in the ATP1A3 gene cause rapid-onset of dystonia parkinsonism (RDP), a rare movement disorder characterized by sudden onset of dystonic spasms and slowness of movement. To achieve a better understanding of the pathophysiology of the disease, we used immunohistochemical approaches to describe the regional and cellular distribution of ATP1 alpha(3) in the adult mouse brain. Our results show that localization of ATP1 alpha(3) is restricted to neurons, and it is expressed mostly in projections (fibers and punctuates), but cell body expression is also observed. We found high expression of ATP1 alpha(3) in GABAergic neurons in all nuclei of the basal ganglia (striatum, globus pallidus, subthalamic nucleus, and substantia nigra), which is a key circuitry in the fine movement control. Several thalamic nuclei structures harboring connections to and from the cortex expressed high levels of the ATP1 alpha(3) isoform. Other structures with high expression of ATP1 alpha(3) included cerebellum, red nucleus, and several areas of the pons (reticulotegmental nucleus of pons). We also found high expression of ATP1 alpha(3) in projections and cell bodies in hippocampus; most of these ATP1 alpha(3)-positive cell bodies showed colocalization to GABAergic neurons. ATP1 alpha(3) expression was not significant in the dopaminergic cells of substantia nigra. In conclusion, and based on our data, ATP1 alpha(3) is widely expressed in neuronal populations but mainly in GABAergic neurons in areas and nuclei related to movement control, in agreement with RDP symptoms. J. Comp. Neurol. 519:376-404, 2011. (C) 2010 Wiley-Liss, Inc.