- Parkinson’s disease is the second most common neurodegenerative disorder worldwide, affecting more than 10 million people.
- Symptoms include tremor, and problems with movement, balance and coordination.
- Experts believe it is caused by death of dopamine-containing nerve cells in the region of the brain involved in motor control.
- Now, a recent study suggests that synapses — the connections between these nerve cells — may start to become dysfunctional before the nerve cells are affected.
- The authors suggest that new treatment strategies could target the synapses before neurons are affected.
Parkinson’s disease is a relatively common neurodegenerative disorder, second only to Alzheimer’s disease in frequency.
Worldwide, it affects more than 10 million people and around 1 million people have the condition in the United States alone. Although not fatal, it is a progressive, chronic condition.
Parkinson’s disease is more common in men than in women, and the risk of developing the condition increases with age.
Some 10–15% of those with Parkinson’s disease have a genetic predisposition for it. In others, the cause is unclear, but environmental factors, such as chemicals, toxins, and head trauma, may increase the risk.
Symptoms, which include slowing of movements, resting tremor or rigidity, sleep dysfunction, and mood disorders, are largely due to low levels of the
These low dopamine levels have long been thought to result from the death of dopamine-containing neurons (nerve cells) in the
Now, researchers have discovered that the interaction of two genes may disrupt the function of the synapses between these dopaminergic neurons before the nerve cells themselves are affected.
They suggest that by targeting the synapses, treatments may be able to prevent damage to the neurons, thereby slowing progression of the disease.
The study appears in the journal
The research was prompted by evidence from two sisters who developed early-onset Parkinson’s disease. Both had inherited a genetic susceptibility from their parents, with one developing Parkinson’s disease at the age of 16 and the other at 49.
The researchers found that both sisters had a loss-of-function mutation in a gene that typically has a neuroprotective role — the
In addition, the sister diagnosed at 16 had inherited a mutation that led to a partial loss of another gene —
PINK1 and parkin together are involved in removing or recycling worn out mitochondria — the cell’s energy producers — in the synapse.
People with mutations in both copies of either gene are unable to recycle and remove defective mitochondria, and develop Parkinson’s disease.
Partial loss of parkin does not usually lead to Parkinson’s disease, so the researchers investigated further. They discovered that parkin, but not PINK1, is also involved in another pathway in the synaptic terminal — controlling the release of dopamine.
Mutant parkin leads to defective recycling of vesicles, leading to less dopamine being released and toxic
In the sister with both mutations, the researchers found much higher levels of oxidized dopamine, suggesting that her partial loss of parkin contributed to this increase.
The researchers suggest that the lack of parkin acts in addition to the deficits in PINK1/parkin-mediated mitochondrial quality control, to help drive synaptic dysfunction in Parkinson’s disease.
Dr. Michael S. Okun, national medical advisor at Parkinson’s Foundation, and director of the Norman Fixel Institute for Neurological Diseases at the University of Florida, not involved in this research, explained to Medical News Today:
“This study revealed that neurons from folks with Parkinson’s who also had a mutation in the parkin gene manifested difficulties in recycling synaptic vesicles. Synaptic vesicles are important as they store the chemicals in the brain which are critically needed for nerve transmission. The folks in this study accumulated toxic oxidized dopamine as a result of this abnormality.”
“The authors performed a very interesting experiment where they combined parkin and PINK1 mutations, and they were able to show earlier disease onset and an independent role the PINK1 gene had in contributing to Parkinson’s disease,” Dr. Okun added.
In the paper, the authors state that “synaptic dysfunction may represent an initial pathogenic event” in Parkinson’s disease.
This means that synapses become affected before the death of dopaminergic neurons, which experts have long believed to cause Parkinson’s disease symptoms.
Corresponding author Prof. Dimitri Krainc, the Aaron Montgomery Ward Professor and chair of The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, told MNT that “[the] clinical implications are that we have to intervene early before neurons degenerate, by targeting synaptic dysfunction.”
At present, treatments for Parkinson’s disease depend on the symptoms being experienced, but many aim to increase levels of dopamine.
Levodopa, which is converted into dopamine in the body, is the most commonly prescribed drug, but it can have unpleasant side effects. An alternative is monoamine oxidase-b (MAO-B) inhibitors that prevent breakdown of dopamine by the enzyme MAO-B, so preserving dopamine levels in the brain.
This new finding suggests that therapies that target the parkin pathway may be a way of treating Parkinson’s disease before dopaminergic neurons start to die, as Prof. Krainc told MNT.
“We are exploring therapeutic options to target this pathway in genetic and sporadic forms of Parkinson’s disease,” he told us.
Dr. Okun noted that “[w]hat is very interesting about this study is that a pathway was uncovered which selectively activates parkin in the location of the human dopamine-containing synapse.“
“We are left to wonder whether this study has uncovered a clue in Parkinson’s disease pathogenesis,” he said.
