Scientists have identified a toxic cascade that results in neuronal degeneration in people with Parkinson’s disease (PD) and have determined how to interrupt it, reports a study published in the journal Science.
Using an antioxidant to intervene early in the disease process may break the cycle of degeneration and improve the function of neurons in Parkinson’s, according to the study.
Using human neurons from Parkinson’s patients, the scientists identified a toxic cascade of mitochondrial and lysosomal dysfunction initiated by an accumulation of oxidized dopamine and a protein called alpha-synuclein. The study demonstrated that an accumulation of oxidized dopamine depressed the activity of lysosomal glucocerebrosidase (GCase), an enzyme implicated in PD. That depression in turn weakened overall lysosomal function and contributed to degeneration of neurons.
The accretion of oxidized dopamine didn’t just interfere with lysosomes, however. The scientists discovered that the dopamine also damaged the neurons’ mitochondria by increasing mitochondrial oxidant stress. These dysfunctional mitochondria led to increased oxidized dopamine levels, creating a vicious cycle.
After identifying the toxic cascade, the researchers looked for ways to disrupt it. They noted that by treating dopamine neurons with specific antioxidants early in the toxic cascade process attenuated or even prevented the downstream effects in human dopaminergic neurons. This approach may be a future therapy target. However, since neurodegeneration creates damage before symptoms are apparent, an antioxidant therapy may also require genetic testing and other screening measures such as brain imaging and other clinical signifiers to identify patients in the early stages of the disease.
Paper: “Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease”
Reprinted from materials provided by Northwestern University.