The molecule, called cardiolipin, is an essential component of the membrane of the mitochondria, which are the tiny “power plants” inside cells that give them energy and help move their metabolism.
Lewy bodies are a feature of Parkinson's disease. They contain toxic clusters of alpha-synuclein and other proteins that have not folded properly.
In a paper recently published in the journal Nature Communications, researchers from the’University of Guelph in Canada describe how they discovered “a new mechanism” in which cardiolipin folds alpha-synuclein.
They also found that cardiolipin “can extract” alpha-synuclein from toxic clusters and fold it, “thus effectively buffering,” or delaying, the progress of the protein's toxicity.
Senior study author Scott D. Ryan, professor in the Department of Molecular and Cellular Biology at the University, he observes:
“Identifying the crucial role of cardiolipin in maintaining functional alpha-synuclein means that cardiolipin could be of interest in new studies for the development of therapies against Parkinson's disease.”
The mechanism of alpha-synuclein is unclear
Parkinson's disease is a degenerative disease that worsens over time. The most common symptoms of the disease include tremors, muscle rigidity, impaired balance and coordination, and slowness of movement.
It also has nonmovement-related symptoms, such as anxiety, depression, sleep disturbances, constipation, and fatigue.
There are more than 10 million people worldwide living with this condition, including about 300,000 cases in Italy. The disease mostly strikes after age 50, although in 10% of cases, it can occur earlier.
The main difference between Parkinson's disease and other movement disorders is that the former is caused by the death of certain cells in the substantia nigra that are involved in producing dopamine.
Dopamine and its role in Parkinson's disease
Dopamine is a messenger molecule, or neurotransmitter, that helps control movement. Many Parkinson's treatments aim to increase brain levels of dopamine.
Although misfolded alpha-synuclein is a hallmark of Lewy bodies-whose presence in Parkinson's disease precedes dopamine cell death-the specific mechanism is somewhat unclear.
However, what we do know is that in its normal form, alpha-synuclein appears to be important for the proper functioning of cells.
For example, there is evidence to suggest that alpha-synuclein is important for the storage and recycling of neurotransmitters and may also be involved in the control of enzymes that increase dopamine levels.
The effect of cardiolipin is reduced in brain cells
In order to find out how brain cells deal with incorrect alpha-synuclein folding, the Prof. Ryan and his colleagues conducted experiments using human stem cells.
“We thought that if we could better understand how cells normally fold alpha-synuclein, we might be able to harness that process to dissolve these aggregates and slow the spread of the disease.”.
The researchers compared normal stem cells with those of people with Parkinson's disease who had a mutated version of the alpha-synuclein gene.
Through these experiments, the team found that alpha-synuclein attaches to mitochondria inside brain cells and that cardiolipin in mitochondria folds the protein correctly into “non-toxic forms,” thus delaying the process of alpha-synuclein toxicity.
The scientists also found that “buffering capacity is reduced” in cells that have the mutated forms of alpha-synuclein due to familiarity with the disease.
Therefore, the researchers speculate that cardiolipin's ability to slow or halt the progress of alpha-synuclein toxicity is eventually overwhelmed and leads to cell death in people with Parkinson's disease.
They believe their findings could lead to a new drug that slows disease progression by targeting the role of cardiolipin in alpha-synuclein folding.
“The hope is that we will be able to preserve motor deficits in animal tests-this is a big step toward treating the cause of this disease.”.
“Based on this result, we now have a better understanding of why nerve cells die in Parkinson's disease and how we might be able to intervene.“.
Prof. Scott D. Ryan
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