Better drugs to treat Parkinson’s disease could eventually result from new Israeli/American research on its origins
More than 10 million people around the world have been diagnosed with Parkinson’s disease – the second most common neurodegenerative disorder after Alzheimer’s disease. A brain disease, Parkinson’s causes shaking, stiffness, and difficulty with walking, balance and coordination.
Other symptoms may include depression and other emotional changes, difficulty swallowing, chewing, and speaking, urinary problems or constipation, skin problems, and disrupted sleep. Sufferers often develop a “parkinsonian gait” that includes a tendency to lean forward, small quick steps as if hurrying forward, and reduced swinging of the arms. They also may have trouble initiating or continuing movement.
Symptoms often begin on one side of the body or even in one limb on one side of the body. As the disease progresses, it eventually affects both sides. However, the symptoms may still be more severe on one side than on the other.
The symptoms usually begin gradually and get worse over time. As the disease progresses, people may have difficulty walking and talking. They may also have mental and behavioral changes, sleep problems, depression, memory difficulties, and fatigue. It affects both men and women, but it affects about 50% more men than women.
One clear risk factor for Parkinson’s is age. Although most people with Parkinson’s first develop the disease at about age 60, about five percent to 10% of people who have contracted it have early-onset disease that begins before the age of 50. These forms of Parkinson’s are often but not always, inherited and some forms have been linked to specific gene mutations.
Parkinson’s disease occurs when nerve cells (neurons) in an area of the brain that controls movement become impaired and/or die. Normally, these neurons produce an important brain chemical known as dopamine. When the neurons die or become impaired, they produce less dopamine, which causes the movement problems of the disease. Doctors still do not know what causes cells that produce dopamine to die.
To better understand the origins of the disease, a team of researchers from the Hebrew University of Jerusalem (HUJI)and Pennsylvania State College of Medicine have developed an integrative approach –
combining experimental and computational methods to understand how individual proteins may form harmful groupings (aggregates) that are known to contribute to the development of the disease. They said their findings could guide the development of new therapeutics to delay or even halt the progression of neurodegenerative diseases.
Alpha-synuclein is a protein that helps regulate the release of neurotransmitters in the brain and is found in neurons. It exists as a single unit but commonly joins together with other units to perform cellular functions. When too many units combine, it can lead to the formation of Lewy bodies, which are associated with neurodegenerative diseases like Parkinson’s and dementia. The team has just published in the journal Structure under the title “The structural heterogeneity of α-synuclein is governed by several distinct subpopulations with interconversion times slower than milliseconds” details about how they studied the different conformations of alpha-synuclein.
Although researchers know that aggregates of this protein cause disease, how they form is not well understood. Alpha-synuclein is highly disordered, meaning it exists as an ensemble of different conformations, or shapes, rather than a well-folded 3D structure. This characteristic makes the protein difficult to study using standard laboratory techniques – but the research team used computers together with leading-edge experiments to predict and study the different conformations it may fold into.
“Computational biology allows us to study how forces within and outside of a protein may act on it,” said pharmacology Prof. Nikolay Dokholyan at the College of Medicine and Penn State Cancer Institute. “Using experiments performed in Prof. Eitan Lerner’s laboratory at the HUJI’s biological chemistry department, a series of algorithms account for effective forces acting in and upon a specific protein and can identify the various conformations it will take based on those forces. This allows us to study the conformations of alpha-synuclein in a way that is otherwise difficult to identify in experimental studies alone.”
They used data from previous experiments to program the molecular dynamics of the protein into their calculations. Their experiments revealed the conformational ensemble of alpha-synuclein, which is a series of different shapes the protein can assume.
Using leading-edge experiments, the researchers found that some shapes of alpha-synuclein are surprisingly stable and last longer than milliseconds. They said this is much slower than estimates of a disordered protein that constantly changes conformations. “Prior knowledge showed this spaghetti-like protein would undergo structure changes in microseconds,” Lerner said. “Our results indicate that alpha-synuclein is stable in some conformations for milliseconds – slower than previously estimated.”
“We believe that we’ve identified stable forms of alpha-synuclein that allow it to form complexes with itself and other biomolecules,” said Jiaxing Chen, a graduate student at Penn State’s College of Medicine. “This opens up possibilities for the development of drugs that can regulate the function of this protein.”
Chen’s lead co-author, Sofia Zaer, alongside HUJI colleagues, used a series of experimental techniques to verify that alpha-synuclein could fold into the stable forms the simulation predicted. The research team continues to study these stable conformations as well as the whole process of alpha-synuclein aggregation in the context of Parkinson’s disease.
“The information from our study could be used to develop small molecule regulators of alpha-synuclein activity,” Lerner concluded. “Drugs that prevent protein aggregation and enhance its normal neuro-physiological function could interfere with the development and progression of neurodegenerative diseases.”
Israel in the News
