Alpha-synuclein rehabilitation?
Parkinson's disease and alpha-synuclein phosphorylation: verdict "not guilty"
LifeSciencesToday based on EPFL – Non coupable materials: Parkinson et la phosphorylation des proteinsAccording to scientists of the Federal Polytechnic School of Lausanne (EPFL), who study Parkinson's disease, evidence left at the crime scene does not always point to its culprit.
It is generally accepted that Parkinson's disease is complicated by phosphorylation of the alpha-synuclein protein. Swiss neurophysiologists managed to show that everything happens "exactly the opposite": phosphorylation of alpha-synuclein protects the body from further progression of the disease. This unexpected discovery could radically change the therapeutic approaches currently being developed by pharmaceutical companies.
Parkinson's disease is characterized by the accumulation in the brain of a protein known as alpha-synuclein. With increased synthesis or violation of autophagy processes, that is, its timely destruction, alpha-synuclein forms small clusters inside neurons, which eventually cause the death of nerve cells. A few years ago, scientists established that before the formation of aggregates, alpha-synuclein undergoes phosphorylation, a process during which a certain enzyme attaches phosphate groups to a protein that change its properties.
The conclusion of scientists that the activity of the enzyme that carries out the phosphorylation of alpha-synuclein is responsible for the development of Parkinson's disease seems quite reasonable: if phosphorylation and protein aggregation go "hand in hand", it is likely that one is the cause of the other. Based on this assumption, scientists and pharmaceutical companies are trying to suppress the phosphorylation of alpha-synuclein by inhibiting the enzyme involved in this process. But, as EPFL researchers have shown, they are on the wrong track.
Moreover, in their opinion, phosphorylation of alpha-synuclein has positive consequences for the cell. On the one hand, it significantly reduces the toxic aggregation of protein, and on the other hand, it helps the cell to eliminate it. These two phenomena are undoubtedly related and together may play a role in reducing the toxicity of alpha-synuclein, but scientists do not yet understand exactly how they affect each of the stages of the disease.
To come to such conclusions, biologists had to investigate the initial stages of the development of Parkinson's disease. They injected substances into rat neurons that are considered triggers of overexpression of alpha-synuclein and its phosphorylating enzyme PLK2 (Polo-like kinase 2).
To their surprise, the rats of the first group, who were injected with compounds that enhance both protein production and its phosphorylation, lost significantly fewer neurons (by about 70%) than the animals of the second group, in which only the expression of alpha-synuclein was increased. As a result, the symptoms of Parkinson's disease were less pronounced in the first group.
"Our study showed the limitations of the most commonly used approach, in which genetic mutations are used to simulate this process," explains Associate Professor Hilal Lashuel, who led the study.
Professor Lachuel considers it very likely that phosphorylation of alpha-synuclein molecules occurs after their aggregation, that is, when the pathology is already well expressed. But it can also be a mechanism for protecting neurons, an attempt to slow down the progression of the disease from its very beginning.
A study by Swiss scientists published in the journal Proceedings of the National Academy of Sciences (Oueslati et al., Polo-like kinase 2 regulates selective autophagic alfa-synuclein clearance and suppresses its toxicity in vivo) paves the way for the development of more advanced drugs.
"The lesson we have learned from this study is that not everything that is at the crime scene is directly related to it. If we fixate on this assumption, we may lose sight of the big picture," Lachuel concludes.
Portal "Eternal youth" http://vechnayamolodost.ru03.09.2013