Researchers at Mount Sinai Hospital and Columbia University have characterized the variations in the processing of RNA in a brain region especially affected by Alzheimer's disease and concluded that alterations in the alternative processing of RNA are a characteristic molecular feature of this disease.
The alternative processing of RNA is the molecular mechanism that allows the cells of our body to be able to produce more than 30,000 different proteins, from the approximately 18,000 protein-coding genes that our genome has. The alternative processing consists in the selective elimination or inclusion of some exons and not others in the messenger RNA of the same gene, a kind of short stick that maintains the RNA sequences necessary for the synthesis of a specific protein. Mutations that alter alternative processing or the machinery responsible for carrying it out can cause diseases. For example, various alterations in RNA metabolism have been related to neurodegenerative diseases such as Parkinson's or Alzheimer's. However, in the latter case there was not, until now, an exhaustive record of all the variation in RNA processing that can be found in patients or their differences with respect to healthy people.
What was this investigation? The researchers analyzed gene activity in the dorsolateral prefrontal cortex, one of the first regions affected in Alzheimer's disease, in post-mortem tissue samples of 450 people and obtained a detailed map of the variation in alternative RNA processing. This map allowed, first, to discover hundreds of alterations in the processing of messenger RNA associated with Alzheimer's disease and its pathology. In addition, when contrasting the information of alternative processing with that corresponding to genetic variation, the researchers developed a catalog of genetic variants that influence the alternative processing of messenger RNA from more than 3,000 genes in brain tissue.
The researchers also conducted an association study with alternative transcription and processing information regarding the presence or absence of disease. This analysis allowed the identification of 21 genes related to Alzheimer's disease, eight of them without previous relation to the disease. These genes point, among other molecular routes, to a participation of those related to the degradation and recycling of proteins in the disease.
What is the Importance of these results? The researchers consider their reference map as a tool of great value. "Our reference map of alternative RNA processing in the complete transcriptome in the cerebral cortex with age is a new resource that provides knowledge for many different neurological and psychiatric diseases," says Philip De Jager, director of the Center for Translational Neuroimmunology and Computational of the University of Columbia and one of the directors of the work. "For example, we defined the mechanism of three of the genetic variants that contribute to Alzheimer's susceptibility. These variants change the proportion of different versions of Alzheimer's target genes, resulting in altered cell function and, ultimately, in the accumulation of neuropathology. "
The results of the work suggest that alterations in alternative processing are characteristic of Alzheimer's disease. This circumstance offers a possible new strategy to recover the correct processing of the messenger RNA. "This new knowledge of the genetic mechanisms that occur in the brain with aging will help to offer new strategies and directions for biomarkers aimed at RNA and therapeutic intervention in Alzheimer's disease," says Towfique Raj, a researcher in the Department of Neuroscience and Genetic and Genomic Sciences of the Mount Sinai Hospital. The researcher points out that antisense oligonucleotides that already offer promising results in neurodegenerative diseases such as spinal muscular atrophy, could become an option also in Alzheimer's.
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