The variety of symptoms of Parkinson's disease has been explained
The symptoms of Parkinson's disease depend on the structure of alpha-synuclein aggregates
LifeSciencesToday based on CNRS materials: Two forms of Parkinson's disease identifiedWhy are the symptoms of Parkinson's disease so diverse?
A consortium of scientists led by a group from the Laboratory of Enzymology and Structural Biochemistry of the National Center for Scientific Research (Le Centre national de la recherche scientifique), France, most likely knows what explains this phenomenon.
Parkinson's disease is caused by a protein known as alpha-synuclein, which forms aggregates in neurons, eventually killing them. The researchers were able to describe and obtain two different types of alpha-synuclein aggregates. Moreover, they showed that one of these two forms is much more toxic and has a more pronounced ability to damage neurons. This discovery explains the existing differences in the profiles of alpha-synuclein accumulation in different patients at the molecular level. The results of the study, published in the journal Nature Communications (Bousset et al., Structural and functional characterization of two alpha-synuclein strains), represent a significant step forward in our understanding of Parkinson's disease and pave the way for the development of specific treatments focused on each of the forms of the disease.
Parkinson's disease – the second most common neurodegenerative disease after Alzheimer's disease – affects about 150 thousand people in France. The disease can manifest itself in the form of uncontrolled tremor (in 60% of patients) or less localized symptoms, such as depression, behavioral and motor disorders. These differences in symptoms indicate the existence of different forms of the disease.
Parkinson's disease, an incurable disease today, is associated with aggregation in the form of fibrillar clusters of alpha–synuclein protein, normally present in high concentrations at the endings of the processes of neurons. Aggregates of improperly folded alpha-synuclein spread from neuron to neuron. Having captured a new neuron, they recruit normal alpha-synuclein and add it to the aggregate. Therefore, many scientists are of the opinion that alpha-synuclein aggregates should be considered infectious proteins, in other words, prions. Highly toxic accumulations of alpha-synuclein eventually trigger the process of apoptosis, that is, cell death.
Negatively colored fibrils (c) and ribbons (d) of alpha-synuclein (Nature Communications)Researchers have shown that there is more than one type of aggregates.
They managed to get two of them, differing only in protein folding. On the scale of millionths of a millimeter, the first form of aggregates looks like spaghetti, while the second – long and flat – rather resembles Italian linguini noodles.
Scientists have tried to determine whether these structural differences lead to functional ones. To get an answer to this question, they used a culture of nerve cells. As it turned out, the ability of the "spaghetti" form to bind and penetrate into cells is noticeably higher than that of the "linguini" form. In addition, the "spaghetti" form is much more toxic and quickly kills infected cells. This form has shown itself capable of resisting the cellular mechanisms responsible for its removal, while the "linguine" form, to a certain extent, is controlled by the cell.
Alpha-synuclein is assembled into two types of aggregates. On the scale of millionths of a millimeter, one of the types of aggregates has the shape of spaghetti. The other, flatter, resembles linguini. These two forms also differ functionally (in binding to cells, toxicity, resistance and spread).
Researchers are convinced that the existence of at least two forms of alpha-synuclein aggregates explains why doctors face significant differences in the symptoms of Parkinson's disease. They are currently conducting experiments on mice to confirm their hypothesis. In their opinion, the analysis of aggregate types can lead to an effective diagnostic method, which, in particular, will allow assessing the virulence of the disease for each patient. Finally, they hope that clarifying the structure of aggregates will make it possible to develop targeted therapeutic strategies for each of their variants in order to slow down the spread of abnormal alpha-synuclein through the brain.
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