Two forms of Parkinson's disease identified

October 14, 2013

Why can the symptoms of Parkinson's disease vary so greatly from one patient to another? A consortium of researchers, headed by a team from the Laboratoire CNRS d'Enzymologie et Biochimie Structurales, is well on the way to providing an explanation. Parkinson's disease is caused by a protein known as alpha-synuclein, which forms aggregates within neurons, killing them eventually. The researchers have succeeded in characterizing and producing two different types of alpha-synuclein aggregates. Better still, they have shown that one of these two forms is much more toxic than the other and has a greater capacity to invade neurons. This discovery takes account, at the molecular scale, of the existence of alpha-synuclein accumulation profiles that differ from one patient to the next. These results, published on October 10 in Nature Communications, represent a notable advance in our understanding of Parkinson's disease and pave the way for the development of specific therapies targeting each form of the disease.

Parkinson's disease, which is the second most frequent neurodegenerative disease after Alzheimer's, affects some 150,000 people in France. According to those suffering from the disease, it can manifest itself in the form of uncontrollable shaking (in 60% of patients) or by less-localized symptoms such as depression, behavioral and motor disorders. These differences in symptoms point to different forms of Parkinson's disease.

This condition, for which no curative treatment currently exists, is caused by the aggregation in the form of fibrillar deposits of alpha-synuclein, a protein that is naturally abundant at neuron junctions. These misfolded alpha-synuclein aggregates propagate between . When they invade a new neuron, they are capable of recruiting normal alpha-synuclein and adding it to the deposit. For this reason, many researchers advocate that the alpha-synuclein of the aggregates should be considered as an infectious protein, in other words a prion. Highly toxic, the alpha-synuclein deposits end up by triggering a process of apoptosis, i.e. cell death.

The researchers have shown that there is not just one single type of aggregate. They succeeded in producing two types of aggregate that only differ in how the protein stacks up. At the millionth of a millimeter scale, the first form of aggregate resembles spaghetti, whereas the second form is long and flat, recalling the shape of wider pasta such as linguine. The team of scientists then tried to determine whether these structural differences result in functional differences. To find out, they placed the two types of aggregates in contact with neuronal cells in culture. They discovered that the capacity of the "spaghetti" form to bind to and penetrate cells is notably greater than that of the "linguine" form. The "spaghetti" form is also considerably more toxic and rapidly kills the infected cells. This form has shown itself to be capable of resisting the cell mechanisms responsible for eliminating it, whereas the "linguine" form is, to a certain extent, controlled by the cell.

The researchers are convinced that the existence of at least two forms of alpha-synuclein aggregates explains why doctors are faced with different Parkinson's diseases depending on the patient. Experiments on mice are currently underway to confirm this hypothesis. Furthermore, the scientists consider that analysis of the type of aggregate could lead to an efficient diagnosis method, which would make it possible in particular to assess the virulence of the disease for each patient. Finally, they hope that by refining the characterization of the structure of the aggregates, it will be possible to develop targeted therapeutic strategies for each variant in order to slow down the propagation of abnormal alpha-synuclein within the brain.

Explore further: Shape-shifting disease proteins may explain variable appearance of neurodegenerative diseases

More information: Bousset, L. et al. Structural and functional characterization of two alpha-synuclein strains, Nature Communications, 10 October 2013. DOI: 10.1038/ncomms3575

Related Stories

Shape-shifting disease proteins may explain variable appearance of neurodegenerative diseases

July 3, 2013
Neurodegenerative diseases are not all alike. Two individuals suffering from the same disease may experience very different age of onset, symptoms, severity, and constellation of impairments, as well as different rates of ...

Study identifies possible biomarker for Parkinson's disease

October 7, 2013
Although Parkinson's disease is the second most prevalent neurodegenerative disorder in the U.S., there are no standard clinical tests available to identify this widespread condition. As a result, Parkinson's disease often ...

Study shows how Parkinson's disease protein acts like a virus

April 25, 2013
A protein known to be a key player in the development of Parkinson's disease is able to enter and harm cells in the same way that viruses do, according to a Loyola University Chicago Stritch School of Medicine study.

SUMO defeats protein aggregates that typify Parkinson's disease

July 11, 2011
A small protein called SUMO might prevent the protein aggregations that typify Parkinson's disease (PD), according to a new study in the July 11, 2011, issue of The Journal of Cell Biology.

How Parkinson's disease starts and spreads

April 16, 2012
Injection of a small amount of clumped protein triggers a cascade of events leading to a Parkinson's-like disease in mice, according to an article published online this week in the Journal of Experimental Medicine.

Mechanism that leads to sporadic Parkinson's disease identified

September 25, 2012
Researchers in the Taub Institute at Columbia University Medical Center (CUMC) have identified a mechanism that appears to underlie the common sporadic (non-familial) form of Parkinson's disease, the progressive movement ...

Recommended for you

Scientists solve 3-D structure of key defense protein against Parkinson's disease

October 5, 2017
Scientists at the University of Dundee have identified the structure of a key enzyme that protects the brain against Parkinson's disease.

Novel protein interactions explain memory deficits in Parkinson's disease

September 26, 2017
A study published in the journal Nature Neuroscience describes the identification of a novel molecular pathway that can constitute a therapeutic target for cognitive defects in Parkinson's disease. The study showed that abnormal ...

Psychosis in Parkinson's dementia—new treatment provides hope

September 25, 2017
New research involving King's College London and the University of Exeter has highlighted the benefits of a promising new treatment which could relieve psychosis in thousands of people with dementia related to Parkinson's ...

Bicycling 'overloads' movement networks with Parkinson's

September 23, 2017
(HealthDay)—Bicycling suppresses abnormal beta synchrony in the Parkinsonian basal ganglia, according to a study published online Sept. 11 in the Annals of Neurology.

Researchers find new path to promising Parkinson's treatment

September 19, 2017
Three researchers at The University of Alabama are part of work that is leading to a new direction for drug discovery in the quest to treat Parkinson's disease.

Tug of war between Parkinson's protein and growth factor

September 18, 2017
Alpha-synuclein, a sticky and sometimes toxic protein involved in Parkinson's disease (PD), blocks signals from an important brain growth factor, Emory researchers have discovered.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.