Scientists have revised the molecular mechanisms of Parkinson's disease

The protein synuclein responsible for the formation of amyloid deposits in Parkinson's disease in healthy cells exists in a polymeric form, and in order to form a toxic amyloid precipitate, it must first leave the normal protein complexes.

Neurodegenerative diseases are usually associated with the formation of amyloids - deposits of misfolded protein in nerve cells. The correct functioning of the protein molecule entirely depends on its spatial packing, or folding, and violations in the three-dimensional structure of the protein usually lead to diseases of varying severity. Another way of laying can lead to a mutual "sticking together" of protein molecules and the formation of sediment, amyloid strands, which ultimately destroys the cell.

In the case of Parkinson's disease, amyloid clusters in neurons, called Lewy bodies, consist predominantly of the alpha-sinuclein protein. For a long time, it was thought that alpha-synuclein exists in healthy neurons in a well-soluble monomeric form, but if the structure is disturbed (for example, due to a mutation), its molecules begin to uncontrollably and uncontrollably oligomerize - adhere to complexes forming amyloid deposits.

Researchers from the Brigham Hospital in Boston and the Harvard University School of Medicine claim that all this is a perennial misconception. In their opinion, in a healthy cell there are no single molecules of synuclein, but large complexes, which, nevertheless, are very soluble. In this state, the protein is protected from uncontrolled "self-adhesion" and precipitation.

How did the synuclein manage to lead the scientific community for so long? As the authors write in the journal Nature, scientists in a sense are themselves to blame. Synuclein has been treated for a long time with extremely rigid methods: one of its characteristics is resistance to temperature denaturation and chemical detergents. It does not curdle and does not precipitate even when boiling. (And what happens to proteins during boiling is known to everyone - it is enough to boil an egg.) In many ways, because of this, everyone believed that in a living cell it exists in the form of highly soluble single molecules that are not so easy to make oligomerize and fall out in the precipitate. For purely technical reasons, it was easier to isolate it from cells under stringent conditions, and therefore it was always observed in the form of single, monomeric molecules, since intermolecular interactions were violated. But when scientists attempted to obtain this protein from biological material using milder methods, they found that in a healthy cell, synuclein exists in the form of tetramers, that is, four protein molecules connected together.

It is also important that the researchers used human blood and neural tissue cells to isolate and study synuclein, rather than working with the bacterium to produce protein. The experiments showed that the protein in tetrameric form is very resistant to aggregation and precipitation: during the entire experiment, which lasted 10 days, the synuclein tetramers did not show any tendency to form anything amyloid. On the contrary, the synuclein monomers within a few days began to form characteristic clusters, which by the end of the experiment were formed into real amyloid strands.

Consequently, the researchers conclude, in order to precipitate, the synuclein must first monomerize, to leave the tetrameric complexes. So, it is necessary to reconsider the usual methods of therapy used in Parkinson's disease. If earlier all efforts were directed to prevent the polymerization of synuclein, then in the light of the results obtained it is necessary to act just the opposite: to keep the protein in a "healthy" polymer state and to prevent the molecules from leaving tetrameric complexes, so that they do not get a chance to randomly stick together and formation of the notorious amyloid deposits.

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