Medical News Today: Could a probiotic prevent or reverse Parkinson’s?

A new study using a roundworm model of Parkinson's disease found that a probiotic bacterium could prevent, and in some cases reverse, toxic protein buildup.

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Could a probiotic be the key to treating Parkinson's?

Misfolded alpha-synuclein proteins in the brain are the hallmark sign of Parkinson's disease.

Many experts believe that these toxic protein clumps lead to the progressive loss of brain cells that control movement.

But the science is not clear-cut, and the underlying mechanisms that cause Parkinson's remain elusive.

Without an effective way of preventing or curing Parkinson's, treatment primarily focuses on alleviating symptoms.

A recent line of research has been looking into a possible link to the gut microbiome, the trillions of microbial species that populate our intestines.

Could changing a person's gut microbiome be a way of modifying their risk of developing Parkinson's or even serve as an effective treatment?

A group of scientists from the Universities of Edinburgh and Dundee, both in the United Kingdom, set out to investigate.

Maria Doitsidou, a fellow at the University of Edinburgh's Centre for Discovery Brain Sciences, is the senior study author, and the team's research features in the journal Cell Reports.

Probiotic 'inhibits and reverses' aggregation

For their study, Doitsidou and her colleagues used a nematode worm model that scientists had genetically engineered to express a human version of the alpha-synuclein protein.

These worms normally develop aggregates, or clumps, of alpha-synuclein at day 1 of their adulthood, which is 72 hours after they hatch.

However, when the researchers fed worms a diet containing a probiotic bacterial strain called Bacillus subtilis PXN21, they observed "a nearly complete absence of aggregates," as they state in their paper. The worms still produced the alpha-synuclein protein, but it did not aggregate in the same way.

In worms that had already developed protein aggregates, switching their diet to B. subtilis cleared the aggregates from the affected cells.

The team then followed a set of worms through their lifespan and compared a B. subtilis diet with a conventional laboratory diet.

"The maximum number of aggregates reached in animals fed with B. subtilis was far lower than that observed on the [standard] diet, indicating that B. subtilis does not simply delay aggregate formation," the authors explain in the paper.

"B. subtilis PXN21 inhibits and reverses [alpha-synuclein] aggregation in a [roundworm] model," they note.

Is this effect specific for B. subtilis PXN21, though? To answer this question, the team compared a number of different strains of the bacterium and found that they had similar effects.

Several pathways working together

To find out how B. subtilis is able to prevent and clear alpha-synuclein aggregates, the team used RNA sequencing analysis to compare the gene expression of animals receiving a standard diet with that of those receiving the probiotic.

This analysis revealed changes in sphingolipid metabolism. Sphingolipids are a type of fat molecule, and they are important components of the structure of our cell membranes.

"Previous studies suggest that an imbalance of lipids, including ceramides and sphingolipid intermediates, may contribute to the pathology of [Parkinson's disease]," the authors comment in the paper.

Yet, changes in sphingolipid metabolism were not the only pathways that the researchers identified.

They also saw that B. subtilis was able to protect older animals from alpha-synuclein aggregation through both the formation of complex structures called biofilms and the production of nitric oxide. In addition, the team saw changes in the dietary restriction and the insulin-like signaling pathways.

Importantly, when the team switched animals that had first received a standard diet over to a B. subtilis diet, their motor skills improved.

"The results provide an opportunity to investigate how changing the bacteria that make up our gut microbiome affects Parkinson's. The next steps are to confirm these results in mice, followed by fast-tracked clinical trials since the probiotic we tested is already commercially available."

Maria Doitsidou

Original Article

Medical News Today: New study could ‘drastically’ change how we understand Parkinson’s

The hallmark symptoms of Parkinson's disease are motor symptoms that include shaking hands and slowness of movement, but specialists still do not entirely understand what causes this disease. Newly published research may now overturn prevailing notions about key Parkinson's mechanisms.

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Motor symptoms in Parkinson's disease may be due to brain changes that take place than experts had previously thought.

According to official estimates, in 2020, approximately 930,000 people aged 45 years or older in the United States will be living with Parkinson's disease.

Despite the large number of people who live with this condition, researchers are still unsure exactly what causes it, and, to date, they have found no way of reversing it.

The primary symptoms of Parkinson's disease affect movement and include shakiness, slowness of movement, and limb rigidity.

These motor symptoms can seriously affect a person's quality of life, so specialists have put a lot of work into finding ways of lessening their effects.

So far, the prevalent view among Parkinson's disease specialists has been that the motor symptoms occur when dopaminergic neurons — the brain cells that synthesize the chemical messenger dopamine — start dying off abnormally.

Therefore, to try to offset motor symptoms, doctors may prescribe people with Parkinson's disease a drug called levodopa (or L-DOPA), which helps boost the brain's reserve of dopamine.

However, the long-term use of L-DOPA can lead to serious side effects, including erratic, involuntary movements.

But what if motor symptoms do not start with the death of dopaminergic neurons? If this were the case, it could change how researchers and medical practitioners understand Parkinson's disease and the best way of treating it.

Researchers find new mechanism

A new study may now overturn existing notions regarding the cause of motor symptoms. Lead researchers C. Justin Lee, Ph.D., Hoon Ryu, Ph.D., and Sang Ryong Jeon worked with colleagues from the Institute for Basic Science in Daejeon and both the Korea Institute of Science and Technology and the Asan Medical Center in Seoul — all in South Korea.

The research, which appears in the journal Current Biology, found that symptoms of Parkinson's disease appear before the premature death of dopaminergic neurons.

In their study, the investigators worked with mouse models of Parkinson's disease and also analyzed brain samples from both healthy people and people with Parkinson's.

They found that before the dopaminergic neurons die off, they stop functioning — that is, they stop correctly synthesizing dopamine — and this sets off the symptoms associated with Parkinson's disease.

"Everyone has been so trapped in the conventional idea of the neuronal death as the single cause of [Parkinson's disease]. That hampers efforts to investigate roles of other neuronal activities, such as surrounding astrocytes," says Lee.

"The neuronal death ruled out any possibility to reverse [Parkinson's disease]." However, he notes, "[s]ince dormant neurons can be awakened to resume their production capability, this finding will allow us to give [Parkinson's disease] patients hopes to live a new life without [Parkinson's disease]."

Looking at the mouse models of the condition, the researchers saw that astrocytes — star shaped, non-neuronal cells — in the brain started increasing in number when neurons in their vicinity began dying off.

At this point, a key chemical messenger called GABA also starts increasing in the brain, reaching an excessive level and stopping dopaminergic neurons from producing dopamine, though not killing them.

The researchers confirmed that this process occurs not just in animal models, but also in the brains of people with Parkinson's disease.

Hope for better treatments

However, the researchers also found that there is a way to restore the function of affected dopaminergic neurons by stopping astrocytes from synthesizing GABA. Doing this, they saw, also significantly decreased the severity of motor symptoms associated with Parkinson's disease.

Further experiments in rats revealed another way of restoring function in dopaminergic neurons. The researchers inhibited dopamine synthesis in these neurons in otherwise healthy rat brains by using optogenetic tools — technology that uses light to control the activity of living cells.

This action induced Parkinson's-like motor symptoms in the rats. But when the researchers used optogenetic tools once more, this time to restore function in the dormant dopaminergic neurons, the Parkinson's-like symptoms decreased in severity.

"This research refutes the common belief that there is no disease-modifying treatment for [Parkinson's disease] due to its basis on neuronal cell death," emphasizes Ryu. "The significance of this study lies in its potential as the new form of treatment for patients in early stages of [Parkinson's disease]," the researcher adds.

In the future, argues the research team, these findings may lead to better ways of treating Parkinson's disease — ways that may reverse some of the damage to important brain mechanisms.

"So far, it had been firmly believed that idiopathic [Parkinson's disease] is caused by the death of dopaminergic neurons in [the] substantia nigra [a structure of the brain]," notes Jeon.

"However, this research demonstrates that functional inhibition of dopaminergic neurons by surrounding astrocytes is the core cause of [Parkinon's disease]. It should be a drastic turning point in understanding and treating [Parkinson's disease] and possibly other neurodegenerative disease as well."

Sang Ryong Jeon

Original Article