Neuron: New Discovery Subverts Common Understanding of Parkinson's Disease Causation

The degeneration of dopaminergic neurons, widely regarded as the primary cause of Parkinson's disease, has been challenged in a recent study by researchers from Northwestern University in the United States. They found that synaptic dysfunction in neurons leads to a deficiency of dopamine and precedes neural degeneration, contrary to the prevailing notion. This discovery holds promise for opening new avenues in the treatment of the disease. The research findings were published online in the Neuron journal on September 15, 2023, with the title "Parkinson's disease-linked parkin mutation disrupts recycling of synaptic vesicles in human dopaminergic neurons."

Parkinson's disease affects approximately 1-2% of the total population and is primarily characterized by symptoms such as resting tremors, rigidity, and bradykinesia, which result from the gradual loss of dopaminergic neurons in the midbrain.

This new study focused on midbrain neurons derived from patients, which is crucial since the physiological functions of dopaminergic neurons in mice and humans differ, and findings from mouse neurons do not necessarily apply to humans.

The authors discovered that the function of dopamine synapses is abnormal in various forms of genetic Parkinson's disease. This new research, along with recent studies from Krainc's laboratory, addresses a significant gap in the field: how different genes associated with Parkinson's disease lead to the degeneration of human dopaminergic neurons.

Neuronal Recycling Mechanism: Mitophagy

The process of recycling or clearing out these aged mitochondria is called mitophagy. The genes Parkin and PINK1 play a role in this recycling process. Under normal circumstances, PINK1 activates Parkin, which then directs aging mitochondria to the recycling or processing pathway.

It has been confirmed that individuals with mutations in both copies of PINK1 or Parkin suffer from Parkinson's disease due to the failure of mitochondrial self-recycling.

The Story of Two Sisters: Advancing Parkinson's Research Through Their Disease

Two sisters were born without the PINK1 gene, as both their parents lacked one copy of this critical gene. This made them highly susceptible to Parkinson's disease, but one sister was diagnosed at the age of 16, while the other wasn't diagnosed until the age of 48.

Fig.2 Graphical Abstract. (From Neuron, 2023, Doi:10.1016/j.neuron.2023.08.018)

The reason behind this difference led Krainc and his research team to a significant new discovery. The sister diagnosed with Parkinson's disease at 16 also had a partial Parkin gene deletion, which by itself should not lead to the disease.

The result was that these authors realized that the Parkin gene has an additional, previously unknown important role. This gene also functions in another pathway at the synaptic terminals, where it controls the release of dopamine. By gaining new insights into the reasons for the sister's error, they observed an opportunity to enhance Parkin and prevent the degeneration of dopaminergic neurons in Parkinson's disease.

In summary, the study's groundbreaking discovery of a novel mechanism for Parkin activation in patient neurons opens the door to the development of drugs targeting this pathway. These drugs have the potential to correct synaptic dysfunction, offering a promising strategy for preventing neuronal degeneration in Parkinson's disease.