“Traffic jams” that occur along nerve cells in the brain and disrupt the transport of mitochondria were found to be a significant cause of Parkinson’s disease, a study reports.
In particular, researchers found that alpha-synuclein protein aggregates, the hallmark of Parkinson’s, impair the movement of mitochondria, which provide energy to cells. This shortage in the energy supply leads to the loss of synapses, which are the junction between two nerve cells that allows them to communicate, and ultimately causes the death of these nerve cells.
A newly developed compound, not yet tested in clinical trials, was able to clear the alpha-synuclein aggregation, restoring the normal transport of mitochondria.
“Our findings mean we can improve our understanding of the mechanisms that cause Parkinson’s and push forward new strategies for treatment during the progression of the disease,” Iryna Prots, PhD, a researcher at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and the study’s lead author, said in a press release.
The study, “α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies,” was published in the journal Proceedings of the National Academy of Sciences.
Parkinson’s disease belongs to a large family of neurodegenerative disorders characterized by either high levels or an abnormal form of a protein called alpha-synuclein. This protein tends to clump together, giving rise to small fibrils that accumulate and deposit inside brain cells, producing small inclusions called Lewy bodies. These are highly toxic and are responsible for the death of dopamine-producing nerve cells.
To properly function, nerve cells require large amounts of energy. This energy is provided by mitochondria, the small structures responsible for energy production inside all cells, which move around the cell until they reach the place where they are needed. Mechanisms that impair the movement of mitochondria have already been shown to contribute to Parkinson’s disease in a fruit fly model.
It had also been observed, in postmortem brain samples of Parkinson’s patients, that nerve cells containing alpha-synuclein aggregates had impaired transport of proteins along their axons (the long thread-like part of a nerve cell that conducts electrical impulses from the cell body to other cells). However, scientists didn’t know whether accumulation of alpha-synuclein impacts nerve cell transport in Parkinson’s disease.
To study this, FAU researchers used skin cells (called fibroblasts) from a Parkinson’s patient and from a healthy individual to generate a type of stem cell called induced pluripotent stem cells (iPSCs). These cells are able to generate almost any type of cell in the body.
By inducing iPSCs to grow into nerve cells, the team was able to evaluate how increasing alpha-synuclein aggregates impacted their transport capacity along axons.
They found that Parkinson’s nerve cells had higher levels of alpha-synuclein aggregation and impaired axonal transport of mitochondria than healthy controls. These disruptions in mitochondria transport across nerve cells’ axons resulted in a shortage of energy, leading to loss of synapses.
The team then treated the nerve cells with a newly developed compound, called NPT100-18A, designed to reduce alpha-synuclein aggregation. This was able to restore mitochondria transport along axons.
Because alpha-synuclein aggregates and axonal dysfunction are early events in Parkinson’s, these findings may help develop new therapies that target the early stages of the disease.
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