Parkinson's disease is characterized by the loss of dopamine-generating neurons, with the inflammatory pathology leading up to that issue thought to be driven by the spread of misfolded α-synuclein. Dysfunctional mitochondrial quality control can make these dopamine-generating neurons more vulnerable to the underlying pathology, however, and thus a fraction of Parkinson's disease arises in people with mutations that cause this sort of dysfunction. That has directed researchers towards mitochondrial function as an important factor in the progression of the condition, but it will probably turn out to be more useful to focus on the deeper causes, such as inflammation and cell dysfunction driven by α-synuclein aggregation.
Degeneration of dopaminergic neurons is widely accepted as the first event that leads to Parkinson's. But the new study suggests that a dysfunction in the neuron's synapses - the tiny gap across which a neuron can send an impulse to another neuron - leads to deficits in dopamine and precedes the neurodegeneration. The study investigated patient-derived midbrain neurons, which is critical because mouse and human dopamine neurons have a different physiology and findings in the mouse neurons are not translatable to humans.
Imagine two workers in a neuronal recycling plant. It's their job to recycle mitochondria, the energy producers of the cell, that are too old or overworked. If the dysfunctional mitochondria remain in the cell, they can cause cellular dysfunction. The process of recycling or removing these old mitochondria is called mitophagy. The two workers in this recycling process are the genes Parkin and PINK1. In a normal situation, PINK1 activates Parkin to move the old mitochondria into the path to be recycled or disposed of. It has been well-established that people who carry mutations in both copies of either PINK1 or Parkin develop Parkinson's disease because of ineffective mitophagy.
Two sisters had the misfortune of being born without the PINK1 gene, because their parents were each missing a copy of the critical gene. This put the sisters at high risk for Parkinson's disease, but one sister was diagnosed at age 16, while the other was not diagnosed until she was 48. The reason for the disparity led to an important new discovery. The sister who was diagnosed at 16 also had partial loss of Parkin, which, by itself, should not cause Parkinson's.
As a result, the scientists realized that Parkin has another important job that had previously been unknown. The gene also functions in a different pathway in the synaptic terminal - unrelated to its recycling work - where it controls dopamine release. With this new understanding of what went wrong for the sister, scientists saw a new opportunity to boost Parkin and the potential to prevent the degeneration of dopamine neurons. "We discovered a new mechanism to activate Parkin in patient neurons. Now, we need to develop drugs that stimulate this pathway, correct synaptic dysfunction and hopefully prevent neuronal degeneration in Parkinson's."