Combination of genetic and environmental 'hits' required for Parkinson's disease

New research finds that a complex interaction between separate factors underlies the pathology associated with Parkinson's disease (PD), reinforcing the concept that multiple therapeutic targets should be considered when designing treatment strategies. The findings, published by Cell Press in the April 30th issue of the journal Neuron, also help to explain why known risk factors do not predict PD in a straightforward manner. PD is a neurodegenerative disease that impairs movement and is characterized by a specific loss of dopamine neurons in a region of the midbrain called the substantia nigra (SN). Interestingly, dopamine neurons in neighboring brain regions are spared. Research has shown that the SN neurons of PD patients contain ?-synuclein protein and exhibit elevated levels of calcium and free intracellular dopamine (known as "cytosolic" dopamine). However, the specific contributions and interplay of these factors are not well understood.

"Although a long-standing hypothesis of neuronal neurodegeneration in PD postulates that elevated cytosolic dopamine underlies the selective cell death characteristic of PD, it has never been directly studied," explains senior study author, Dr. David Sulzer from the Department of Neurology at Columbia University. "To better understand the pathology of PD, we used a new electrochemical approach to measure cytosolic dopamine in neurons following various pharmacological and genetic interventions."

Dr. Sulzer and colleagues found that in midbrain neurons grown in culture, elevated cytosolic dopamine was toxic to neurons. Genetic and pharmacological interventions which decreased levels of cytosolic dopamine protected the neurons. The characteristic increased susceptibility of SN neurons, and not neighboring neurons, to cytosolic dopamine-related toxicity was dependent on the activity of calcium channels. Further, neurons lacking ?-synuclein were resistant to cytosolic-dopamine-induced cell death.

The results indicate that PD may require multiple steps, some genetic and some environmental. "Based on our findings, we suggest that selective death of SN dopaminergic neurons responsible for the definitive motor deficits in PD can result from a combination of 'multiple hits' resulting from the activity of calcium channels, an increase in cytosolic dopamine and the presence of ?-synuclein," says Dr. Sulzer. "Because interference with any of these three main factors rescued the neurons, it is likely that various strategies could be employed to prevent neuronal death in PD."

Source: Cell Press