Oxidized Dopamine and Dysfunctional Lysosomes in Parkinson's Disease
This research improves on the established links between a few of the forms of molecular damage and cellular dysfunction that central to the SENS view of aging, at least in the case of Parkinson's disease. These are lysosomal failure, mitochondrial dysfunction, and the accumulation of damaged proteins that form solid deposits, alpha-synuclein in this case. All age-related diseases emerge from the various typs of root cause damage that causes aging, some more directly, some with more intervening layers of secondary failure and damage.
Parkinson's disease (PD) is the second most common neurodegenerative disorder, primarily caused by the death of dopamine-containing neurons in the substantia nigra, a region of the brain involved in motor control. While people naturally lose dopamine neurons as they age, patients with PD lose a much larger number of these neurons and the remaining cells are no longer able to compensate. Understanding how and why these neurons die is an important step in identifying treatments. While previous research indicated that the cellular mechanism behind the cell death involved the mitochondria and lysosomes, how these two pathways converge in dopamine neurons to cause cell death remained unknown up until now.
Using human neurons from Parkinson's patients, researchers identified a toxic cascade of mitochondrial and lysosomal dysfunction initiated by an accumulation of oxidized dopamine and a protein called alpha-synuclein. Specifically, the current 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. Researchers discovered that the dopamine also damaged the neurons' mitochondria by increasing mitochondrial oxidative stress. These dysfunctional mitochondria led to increased oxidized dopamine levels, creating a vicious cycle.
"The mitochondrial and lysosomal pathways are two critical pathways in disease development. Combined with the alpha-synuclein accumulation, this study links the major pathological features of PD. One of the key strategies that worked in our experiments is to treat dopamine neurons early in the toxic cascade with specific antioxidants that improve mitochondrial oxidative stress and lower oxidized dopamine. With this approach, we found that we can attenuate or prevent the downstream toxic effects in human dopaminergic neurons." Interestingly, when compared to human cellular models, mouse models of PD did not demonstrate the same toxic cascade. The researchers showed this is due to differences in metabolism of dopamine between species, and underscored the importance of studying human neurons to discover new targets for drug development.
Link: https://news.northwestern.edu/stories/2017/september/interrupting-parkinsons-disease/