The molecule, called cardiolipin, is an essential component of mitochondria membranes, which are the tiny “powerhouses” inside cells, providing them with energy and aiding in their metabolism.
Lewy bodies are a feature of Parkinson’s disease. They contain toxic clumps of alpha-synuclein and other misfolded proteins.
In a recently published article 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 clumps and refold it, “thus effectively buffering,” or slowing down, the progression of protein toxicity.
Lead author Scott D. Ryan, Professor in the Department of Molecular and Cellular Biology at the University, notes:
“Identifying the crucial role of cardiolipin in maintaining functional alpha-synuclein means cardiolipin could be of interest for new studies into developing 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 condition include tremors, muscle rigidity, impaired balance and coordination, and slowness of movement.
It also has non-motor symptoms, such as anxiety, depression, sleep disturbances, constipation, and fatigue.
There are over 10 million people worldwide living with this condition, including approximately 300,000 cases in Italy. The disease mainly affects people over 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 produce dopamine.
Dopamine and its role in Parkinson’s disease
Dopamine is a messenger molecule, or neurotransmitter, that helps control movement. Many treatments for Parkinson’s aim to increase dopamine levels in the brain.
Although misfolded alpha-synuclein is a feature of Lewy bodies – whose presence in Parkinson’s disease precedes the death of dopamine cells – 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 preservation and recycling of neurotransmitters and may also be involved in controlling enzymes that increase dopamine levels.
The effect of cardiolipin is reduced in brain cells
To discover how brain cells deal with the misfolding of alpha-synuclein, 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 from people with Parkinson’s who had a mutated version of the alpha-synuclein gene.
Through these experiments, the team discovered that alpha-synuclein attaches to mitochondria inside brain cells and that cardiolipin in mitochondria correctly folds the protein into “non-toxic forms,” thus delaying the process of alpha-synuclein toxicity.
Scientists also found that the “buffering capacity is reduced” in cells with mutated forms of alpha-synuclein due to a familiarity with the disease.
Therefore, researchers hypothesize that the ability of cardiolipin to slow or halt the progression of alpha-synuclein toxicity is ultimately overwhelmed and leads to cell death in people with Parkinson’s disease.
They believe their findings could lead to a new drug that slows the progression of the disease by targeting the role of cardiolipin in folding alpha-synuclein.
“The hope is that we will be able to preserve motor deficits in animal tests: it’s a big step towards treating the cause of this disease.”
“Based on this outcome, 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
