Alternations Seen in RNA Splicing and Protein Creation in Alzheimer’s Disease

Using a technique called genome-wide mapping, researchers were able to identify specific variations in RNA splicing from brain tissue taken from 450 people who were part of clinical studies into aging.

This work — which identified hundreds of altered splicing events, which affect protein production — in Alzheimer’s, and may offer new ways of diagnosing and treating this disease.

The study, “Integrative transcriptome analyses of the aging brain implicate altered splicing in Alzheimer’s disease susceptibility,” was published in the journal Nature Genetics.

All genetic information contained within genes (DNA) is ultimately translated into proteins. However, several complex steps exist before a protein can be produced.

DNA is transformed into pre-messenger RNA (pre-mRNA), which is then processed to create a mature mRNA — messenger RNA — molecule. This process is called RNA splicing. Once mRNA molecules are produced, a process called translation begins, and it is this process that gives rise to proteins.

During splicing, introns (the part of the pre-mRNA that does not code for proteins) are removed, and exons (the part that does) are joined together. This allows for a single gene to give rise to many different proteins — much like adding certain ingredients to, or leaving them out of, a recipe results in different dishes.

Mutations involved in how splicing is regulated are linked to several diseases, including amyotrophic lateral sclerosis (ALS) and autism.

Researchers at the Icahn School of Medicine at Mount Sinai and Columbia University used a technique called genome-wide mapping to analyze the set of mRNA molecules, the so-called transcriptome, in brain tissues collected in autopsies of older people. All 450 had taken part in either the Religious Order Study (ROS) or the Memory and Aging Project (MAP), two prospective cohort studies of aging that include brain donation.

This mapping allowed the identification of sources of variation in mRNA splicing in the dorsolateral prefrontal cortex (DLPFC) — a part of the prefrontal cortex responsible for executive functions, such as working memory, cognitive flexibility or abstract reasoning — in the brain tissue samples.

They found hundreds of abnormal pre-mRNA splicing events linked to Alzheimer’s disease. Altered splicing was hypothesized to be behind mutations in the PICALM, CLU and PTK2B genes, all of which are known to be associated with Alzheimer’s risk.

Researchers also reported discovering 21 genes with significant associations to Alzheimer’s disease, including eight genes present in previously unknown genetic loci — gene positions within a chromosome.

These genes were found to be related to cell suicide (autophagy) and lysosomal pathways, two mechanisms involved in the onset and progression of Alzheimer’s.

These results provide a comprehensive genome-wide map of RNA splicing variations in the aging brain that may guide research into Alzheimer’s disease.

“Most importantly, these new insights into genetic mechanisms in the aging brain will help offer new strategies and directions for RNA-targeted biomarkers and therapeutic intervention in Alzheimer’s disease,” Towfique Raj, PhD, the study’s first author and assistant professor in the Ronald M. Loeb Center for Alzheimer’s Disease at Mount Sinai, said in a press release.

A class of synthetic compounds called antisense oligonucleotides was also highlighted, and researchers suggested they may be used to target specific RNA sequences (splicing sites) to prevent them from producing a certain protein. “This class of drugs shows promise in treating an array of brain disorders including spinal muscular atrophy, ALS and Huntington’s disease,” Raj said.

“Our transcriptome-wide reference map of RNA splicing in the aging cortex is a new resource that provides insights for many different neurologic and psychiatric diseases,” added Philip de Jager, MD, PhD, a co-corresponding study author and director for the Center of Translational and Computational Neuro-Immunology at Columbia University.

“For example, we define the mechanism for three of the genetic variants [PICALM, CLU and PTK2B] that contribute to Alzheimer’s susceptibility. These variants change the proportion of different versions of the target Alzheimer’s genes, resulting in altered cell function and, ultimately, the accumulation of neuropathology,” de Jager said.