Non-coding RNA contributes to the development of Alzheimer's disease
Researchers from three Italian universities have demonstrated that small RNA 38A triggers the production of Var IV in neurons, a variant of the KCNIP4 protein resulting from alternative splicing. The KCNIP4 protein plays an important role in the functioning of nerve cells, and, apparently, the appearance of its alternative version stimulates the development of Alzheimer's disease and, possibly, other neurodegenerative diseases.
Like films with alternative endings, the process of splicing and folding (cutting and folding into a globule) of amino acid chains can lead to the appearance of several variants of protein molecules. Despite the fact that scientists have identified many proteins and RNAs that affect alternative splicing, they have not yet deciphered the mechanism by which the cell regulates the formation of certain versions of the protein. Four years ago, 30 small non-coding RNAs were identified, presumably involved in regulating the expression of genes related to this mechanism.
In their study, Italian scientists determined the function of one of the small RNAs known as 38A and formed on a non-coding fragment of a protein gene interacting with potassium channels (potassium channel-interacting protein, KCNIP4). This protein is necessary for neurons to maintain a special cycle of slowly repeating electrical impulses. It turned out that 38A triggers the synthesis of an alternative variant of KCNIP4, called Var IV, which disrupts the rhythm of the emission of nerve impulses and possibly contributes to the development of neurodegenerative diseases. The remaining three variants of amino acid sequences in the same section of this protein, despite the differences, do not disrupt the work of potassium channels.
The figure from the JCB article shows all four variants of the KCNIP4 protein.
The letters denote amino acids: M – methionine, N – asparagine, L – leucine, etc.,
in accordance with the classification of the International Union of Theoretical and Applied Chemistry.
Usually, KCNIP4 interacts with gamma secretase, an enzymatic complex involved in the synthesis of beta-amyloid, a protein that accumulates in the brain tissue of patients with Alzheimer's disease. Var IV is unable to enter into this interaction, which apparently disrupts the normal process of beta-amyloid formation.
In support of this hypothesis, the researchers found that in the brain cells of patients with Alzheimer's disease, the concentration of 38A is more than 10 times higher than the level of this RNA in the cells of healthy people: in the image, Var IV (green) prevails in cells producing excess 38A (left), but is practically absent in control cells (right).
Moreover, they were able to demonstrate that an increase in the level of 38A is accompanied by a sharp increase in the synthesis of the more dangerous isoform of beta-amyloid 1-42.
The article by Massone S. et al. "RNA polymerase III drives alternative splicing of the potassium channel–interacting protein contributing to brain complexity and neurodegeneration was published in The Journal of Cell Biology on May 30.
Evgeniya Ryabtseva
Portal "Eternal youth" www.vechnayamolodost.ru based on the materials of Medical Xpress: Noncoding RNA may promote Alzheimer's disease.
06.06.2011