Deleting Specific Region of Alpha-Synuclein Protein May Prevent Parkinson’s Symptoms, Fly Study Suggests

alpha-synuclein study

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.

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Protein Called Scarlet Seen to Protect Dopamine-producing Brain Cells in Early Study

Scarlet protein and dopamine

A protein called scarlet can protect nerve cells from the damaging effects of toxic alpha-synuclein aggregates that occur in Parkinson’s disease, according to results of research into a fruit fly model.

The study, “Neurodegeneration and locomotor dysfunction in Drosophila scarlet mutants,” was published in the Journal of Cell Science.

Fruit flies (Drosophila melanogaster) have proven to be useful models to study Parkinson’s disease. Similar to what happens in humans, progressive loss of dopamine-producing brain cells leads to defects in locomotor function and control.

Lehigh University researchers, along with collaborators at University of Wisconsin-Madison, evaluated the role of a protein called scarlet in a fruit fly model of Parkinson’s disease.

Upon screening a collection of fruit flies that showed degeneration of dopaminergic nerve cells, the team found some with mutations affecting the scarlet gene.

A detailed evaluation showed no significant differences in the number of dopaminergic neurons in the mutant flies compared to wild-type controls on day three. But, by day 18, the mutant flies had evident neurodegenerative onset, and by day 21 they had significantly lower numbers of neurons.

“These results demonstrate that loss of scarlet function is sufficient to promote degeneration of dopaminergic neurons,” the researchers wrote.

Scarlet mutant flies also had a shorter lifespan, with a median survival of 27 days compared to about 40 days in control flies. And these animals also impaired locomotor activity, with substantially climbing ability by day 11 and that continued to show decline by day 18.

To further explore the gene’s role, researchers induced the production of a normal scarlet gene in dopaminergic nerve cells of flies that carried its mutated version.

Using this approach, they were able to prevent neurodegeneration and rescue the progressive climbing defects previously observed. However, the flies’ lifespan was not expanded, which suggests that “Scarlet’s role in longevity requires more than [its presence] in dopaminergic neurons,” the researchers wrote.

Additional analysis revealed that flies that lacked scarlet had higher levels of potentially damaging reactive oxygen elements, also known as ROS. In contrast, flies that had been genetically altered — given a healthy working version of the scarlet gene — had lower ROS levels in the brain.

“Because dopaminergic neurons are particularly vulnerable to oxidative stress,” these findings suggest that scarlet’s role in Parkinson’s could in part be to limiting oxidative stress, the researchers wrote.

Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them. These free radicals, or ROS, are harmful to cells and  associated with a number of diseases, including Parkinson’s.

Researchers also explored the role of the scarlet protein in flies that had been genetically engineered to carry the human alpha-synuclein protein in dopaminergic neurons.

In the presence of alpha-synuclein — either the normal version or two mutated forms linked to familial Parkinson’s disease — flies experienced significant loss of dopamine-producing cells.  But scarlet was present, even together with alpha-synuclein, the loss of dopamine-producing cells was prevented.

“The experiment demonstrated that Scarlet was sufficient in preventing dopaminergic neuron loss, suggesting a neuroprotective function,” Patrick Cunningham, a PhD student at Lehigh University and study author, said in a Journal of Cell Science interview.

“We found that the fruit fly mutant scarlet [gene], commonly associated with a bright red eye color, showed progressive DA [dopaminergic] neuron loss that was accompanied by impaired movement coordination,” Cunningham added. “A mutation causes errors in the protein that is associated with a specific gene; in other words, the scarlet mutant has a dysfunctional Scarlet protein.”

When the protein was added to mutant flies, it’s presence “showed a neuroprotective function by preventing the loss of DA neurons and maintaining movement coordination.”

The presence of scarlet protein, indeed, helped to ease difficulties with motor function — as seen in the climbing problems — that were induced by all three forms of alpha-synuclein.

“The identification of a neuroprotective role for Scarlet should help in characterizing the selective vulnerability of dopaminergic neurons in Parkinson’s disease,” the researchers wrote.

“Thus, investigating mechanisms uncovered here should be helpful for uncovering potential therapeutic targets to prevent the loss of these neurons,” they concluded.

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Defects in Mitochondria May Contribute to Parkinson’s Disease, Study Suggests


Mutations in mitochondria, which result in a shortage of energy, may be an underlying cause of movement difficulties associated with Parkinson’s disease (PD), a study suggests.

The study, “PINK1 Phosphorylates MIC60/Mitofilin to Control Structural Plasticity of Mitochondrial Crista Junctions,” was published in the journal Molecular Cell.

Parkinson’s disease is caused by the death or malfunction of dopaminergic neurons, which regulate muscle movement and coordination. To do their job, these nerve cells require large amounts of energy, provided by mitochondria.

Mitochondria need to move around the cell to reach the place where they are needed to provide the necessary energy to dopaminergic neurons. Inability of mitochondria to do so can have severe consequences.

Researchers have now discovered that an enzyme (protein) called PINK1 plays a key role in mitochondrial function. This enzyme works to stabilize a mitochondrial protein, called MIC60, which is vital for energy production.

To mimic Parkinson’s, the team used fruit flies, whose brains work similarly to humans to control voluntary movement. They tested how several mutations in the PINK1 gene — known to be a cause of familial forms of early-onset Parkinson’s — affected mitochondria function in the flies.

Several of these mutations were highly damaging to the flies, leading to death in adult flies and significantly impairing crawling ability at early developmental stages.

In flies genetically engineered to lack PINK1, reintroducing MIC60 expression restored mitochondria structure and energy production, correcting the flies’ behavioral defects and halting the death of dopaminergic neurons.

“We found that PINK1 is required only in highly energetic regions of the cells,” Xinnan Wang, MD, the study’s lead author and a Stanford neuroscientist, said in a press release.

“This supports the theory that Parkinson’s disease involves local energy shortages inside cells due to mitochochondrial malfunction — and it indicates that targeting mitochondria may have great potential for exploring new therapeutic interventions in Parkinson’s,” she said.

Future research is necessary to discover if mitochondrial structure impairment and function exists in Parkinson’s disease patients and whether it contributes to disease progression.

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Source: Parkinson's News Today