Scientists have now identified a faulty cell process that may be common to different forms of Parkinson’s, and they propose a mechanism through which it might lead to the disease.
This process involves a group of lipids or fatty molecules called ceramides, which are found in cell membranes and play important roles in their function and structure.
A paper that is now published in the journal Cell Metabolism describes how the team — at Baylor College of Medicine in Houston, TX — made the unexpected discovery in a fruit fly model of a faulty gene condition with Parkinson’s-like symptoms.
Previous studies have identified genes and cell defects linked to Parkinson’s disease and other brain disorders with similar symptoms. The researchers suggest that ceramides are the “missing link” than connects them.
“Numerous genes,” claims senior study author Hugo J. Bellen, a professor of molecular and human genetics and neuroscience at Baylor College of Medicine, “have been associated with Parkinson’s disease or Parkinson-like diseases; nevertheless, there is still little understanding of how these genes cause these conditions.”
Parkinson’s disease affects movement and will get worse over time. Its typical symptoms include tremors, muscle stiffness, and slowness. It can also have nonmotor symptoms, such as sleep disruption, depression, anxiety, and fatigue.
There are around 10 million people worldwide with Parkinson’s, with around 1 million living in the United States.
While the disease mostly strikes after the age of 50, there is a form called early onset Parkinson’s that develops in younger people.
The disease develops because of the destruction of nerve cells, or neurons, in a part of the brain that controls movement. The cells produce a chemical called dopamine that carries messages between the brain and the rest of the body that are important for controlling movement.
Parkinsonism is a general term for conditions that produce symptoms that are similar to those of Parkinson’s, particularly slowness of movement, or bradykinesia, which is the “defining feature.” Parkinson’s disease is the most common cause of Parkinsonism.
The study began with research into the human gene PLA2GA6. Mutations of the gene are known to cause Parkinsonism and other disorders involving the loss of brain tissue.
Previous studies have shown that the gene contains instructions for making an enzyme called phospholipase. The enzyme acts on phospholipids, a group of fats known to be important components of the nervous system, but apart from this, not much is known about them.
To study the effects of PLA2GA6 in cells, the researchers used a fruit fly model of Parkinsonism that is made by silencing iPLA2-VIA, which is the fly equivalent of the human gene.
Flies that lacked the gene lived a third as long as normal flies, and their cells displayed similar features as human cells with PLA2G6 mutations.
The researchers also confirmed, in line with previous studies, that youthful mutant flies were healthy but gradually developed neurodegeneration as they aged.
They also found that lack of the gene had two other effects in the flies: they took longer to recover from physical impacts, and they also showed progressive problems with visual response. Both effects suggested nervous system deficiencies.
When they examined the neurons in the eyes of the mutant flies with electron microscopes, the scientists found that their membranes contained abnormal “inclusions,” or lumps, that were not present in the normal flies.
They also found several other abnormalities, including malformed mitochondria and abnormally large lysosomes. Mitochondria are compartments inside cells that make energy for the cell. Abnormalities in mitochondria are often found in Parkinson’s disease.
Lysosomes are another type of compartment inside cells that act as recycling centers for worn-out cell materials, including membranes.
When looking at these results all together, they indicate “that the iPLA2-VIA gene is important to maintain proper membrane structure and shape,” notes Prof. Bellen.
The researchers assumed that because the iPLA2-VIA gene provides instructions for making the enzyme that acts on phospholipids, they would find problems with phospholipids in the flies without the gene. This would then explain the results.
However, to their surprise, the researchers did not find what they expected. The phospholipids in the mutant flies behaved normally.
So, they turned their attention to other lipids, and this is when they noticed abnormally high levels of ceramides in the files that lacked the iPLA2-VIA gene.
They then gave some of the mutant flies drugs that block ceramide production. The team found that, compared with untreated mutant flies, the treated mutant flies had not only lower levels of ceramides in their cells, but they also showed reduced symptoms of neurodegeneration and several other nervous system deficiencies. Their cells also had fewer abnormalities in their lysosomes.
Further investigation revealed that the problem lay in the recovery and recycling of lipids in ceramides. Another cell component called a retromer finds and extracts the lipids before they enter lysosomes for recycling and sends them to the membranes. If the lipids are not extracted, they end up being recycled to produce more ceramide.
If the retromer does not work properly, levels of ceramides will increase, causing stiffness of the cell membranes. This sets up a vicious cycle that further disables the retromer, causing a further rise in ceramide levels. Eventually, this causes neurodegeneration.
In another part of the study, the team confirmed that the mutant flies had lower levels of retromer proteins called VPS35 and VPS26. In normal flies, these attach to iPLA2-VIA protein and help to stabilize retromer function.
Further tests showed that improving retromer function led to reductions in the defects observed in the mutant fruit flies that lacked the iPLA2-VIA gene. “Interestingly,” Prof. Bellen notes, “mutations in the Vps35 gene also cause Parkinson’s disease.”
The researchers replicated the findings using laboratory-grown animal brain cells. They also found that high levels of a protein often found in the brain in Parkinson’s disease, called alpha-synuclein, also causes retromer dysfunction, large lysosomes, and rises in ceramide levels.
The researchers suggest that their findings reveal a new link between previously unconnected features of Parkinson’s disease.
“We think that our work is important because it points to a potential mechanism leading to Parkinsonism and perhaps Parkinson’s disease.”
Prof. Hugo J. Bellen