The cellular pathology of Rapid-Onset Dystonia-Parkinsonism

• Main Author: Casper, C. J.
• Published: University College London (University of London) 2013
• Subjects: 612.8
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.626290

The dystonias are a common group of movement disorders, which are mechanistically poorly understood. Rapid-onset dystonia-parkinsonism (RDP) is a hereditary movement disorder without neurodegeneration resulting from mutations in the ATP1A3 gene encoding the α3-isoform of the Na+/K+ ATPase. RDP patients are generally asymptomatic until a stressful life event triggers disease onset. Basal Ganglia dysfunction has previously been implicated in RDP aaetiology. To investigate the neuronal pathology in RDP we have generated patient-specific induced pluripotent stem cell (iPS) lines and derived mature midbrain dopaminergic neurons. Using functional live- cell imaging, we have shown that RDP neurons show higher intracellular Na+ levels at rest and smaller Na+ signals in response to stimulation by glutamate or KCl. Consistent with this, resting membrane potential in RDP neurons was chronically elevated and cells failed to return to resting potential after stressful depolarisation. Interestingly, spontaneous spiking activity in the absence of stress was normal. Apart from abnormalities in sodium homeostasis, there was reduced uptake of calcium from the cytosol by mitochondria in RDP neurons probably due to a reversal of the mitochondrial sodium/calcium exchanger in response to elevated intracellular calcium levels. Furthermore mitochondrial pathology in RDP included depolarised mitochondrial membrane potential, reduced oxidative phosphorylation and increase ROS production. Stressful depolarisation induced a sharp increase in ROS production. There was a compensatory increase in Krebs cycle activity to counteract energy depletion due to reduced oxidative phosphorylation and marked upregulation in levels of glutathione, an endogenous antioxidant. This high level of compensation may explain the absence of neurodegeneration in RDP. Based on our findings, we suggest antioxidant therapy as a potential treatment to improve neuronal function in RDP patients.