Alpha-synuclein and oxidative stress in neuron's at risk in Parkinson's disease
The formation of alpha-synuclein inclusions is the cardinal pathology of Parkinson’s disease. Their appearance is accompanied by free radical overproduction in affected neurons (such as dopamine cells). Decades of this oxidative stress presumably lead to cell death. However, we do not know whether alpha-synuclein causes oxidative stress per se. Inclusions appear in vagal motoneurons well before dopamine cells are implicated. We recently described how oxidative stress in vagal motoneurons is caused by an excessive influx of calcium ions. We hypothesize that alpha-synuclein causes oxidative stress by engaging this same mechanism. Using advance electrophysiological and brain imaging techniques, we will test whether treatment with calcium channel blockers -- widely used to treat hypertension -- can reduce the putative oxidative stress.
Network underlying the dopamine-acetylcholine balance
The dopamine-acetylcholine balance hypothesis has served for half a century as a widely- accepted clinical model of movement disorders of the basal ganglia (a brain region responsible for habitual behavior and motor plan selection). It states that a delicate balance between dopamine and acetylcholine levels is maintained in the striatum, the main input structure of the basal ganglia. Loss of this balance leads to a hypodopaminergic-hypercholinergic condition in striatum in Parkinson’s disease and to a hyperdopaminergic- hypocholinergic condition in Huntington’s disease. Despite strong evidence for this model, the underlying mechanism of the balance/imbalance is entirely unknown. Based on recent physiological studies, we are testing the hypothesis that the thalamic projection to acetylcholine release neurons in the striatum orchestrates the balance.
Acetylcholine releasing neurons in Huntington's disease
The main population of neurons in the striatum is severely decimated in Huntington’s disease. In contrast, the acetylcholine releasing neurons are relatively spared. Nevertheless, as mentioned above, there is a reduction in biochemical markers of acetylcholine in Huntington’s disease. We are currently studying adaptations in the input to these neurons and their intrinsic activity in models of Huntington's disease that might explain this paradox.
