By deleting a section of alpha-synuclein, a protein that forms damaging clumps in the brains of Parkinson’s disease patients, researchers were able to prevent Parkinson’s-like symptoms in fruit flies, a study reports.
The study, “The Non-amyloidal Component Region of α-Synuclein Is Important for α-Synuclein Transport Within Axons,” was published in the journal Frontiers in Cellular Neuroscience.
Parkinson’s disease is characterized by the buildup of toxic forms of the alpha-synuclein protein within nerve cells, or neurons, causing clumps and blockages that stop these cells from functioning correctly.
Proper transport of alpha-synuclein is thought to be crucial for its localization and function at the synapse — the junction between two nerve cells that allows them to communicate.
A particular section of the alpha-synuclein protein called the non-amyloidal component (NAC) has been linked to the formation of these clumps.
“Previous work has shown that defects in long distance transport within [neurons] occur early in PD [Parkinson’s disease], but how such defects contribute to PD is unknown,” the researchers wrote.
To understand whether the NAC region is involved in alpha-synuclein’s motility, researchers used fruit fly larvae genetically engineered to express higher levels of the human form of alpha-synuclein protein. They then deleted the NAC region in these flies’ alpha-synuclein and studied the resulting animals for signs of Parkinson’s disease.
They observed that excess alpha-synuclein accumulated in clumps and disrupted the normal transport of other proteins along neuronal axons — long projections that conduct electrical impulses away from the neuron’s cell body toward another nerve cell.
To understand how deleting the NAC region affected motor symptoms, the scientists measured how fast the flies were able to crawl. Flies with too much alpha-synuclein crawled at a significantly slower speed than normal flies. This was likely due to the blockages that occur in the neurons. The higher the levels of alpha-synuclein aggregation within neurons, the more aggravated these symptoms became.
Flies that produced too much alpha-synuclein typically showed Parkinson’s-like symptoms, but if the NAC section of alpha-synuclein was deleted, the protein no longer formed clumps within neurons and crawling speeds returned to normal.
“Our work highlights a potential early treatment strategy for Parkinson’s disease that would leverage the use of deletion of the NAC region,” lead investigator Shermali Gunawardena, PhD, associate professor of biological sciences from the University at Buffalo, said in a press release.
Gunawardena and her team were also interested in how alpha-synuclein gets transported along neuron cells. The researchers thought the movement of alpha-synuclein could be linked to how it interacts with neuronal cell membranes.
They found that when they deleted the NAC region, less alpha-synuclein was able to bind to neuronal membranes, preventing it from being transported along axons. Instead, the alpha-synuclein stayed in the wider sections of neurons and did not cause aggregates.
“While further study is needed to isolate the structural details of how the NAC region facilitates [alpha]-syn protein–protein interactions on membranes, taken together our observations indicate that the NAC region plays an essential role in [alpha]-syn associations on axonal membranes and its transport within axons under physiological conditions,” the researchers wrote.
Overall, the work identifies a pathway that can be targeted in early-stage Parkinson’s disease before symptoms such as neuron loss and behavior changes occur.
“One reason this study is important is because it shows rescue of [alpha]-synuclein aggregates, synaptic morphological defects and locomotion defects seen in Parkinson’s disease in the context of a whole organism,” Gunawardena said.