Alzheimer’s Progression Linked To Aberrant Pre-mRNA Splicing

Specific RNA splicing events associated with Alzheimer’s disease progression have been identified in a large-scale analysis of RNA from postmortem human brain tissue. Researchers at the Icahn School of Medicine at Mount Sinai and Columbia University presented a comprehensive genome-wide map of RNA splicing variation in the aging prefrontal cortex that will serve as a new resource for Alzheimer’s research.

RNA splicing is a process that removes non-coding sequences or genes from RNA precursors and joins together the protein-coding sequences, resulting in multiple protein variants being encoded by a single gene. Enormous protein diversity results from RNA splicing. Genetic mutations involved in splicing regulation and aberrant splicing have previously been linked to amyotrophic lateral sclerosis (ALS) and autism.

“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,”

said the study’s first and co-corresponding author, Towfique Raj, Ph.D., Assistant Professor in the Ronald M. Loeb Center for Alzheimer’s Disease, Departments of Neuroscience and Genetics and Genomic Sciences at Mount Sinai.

Antisense Oligonucleotides

A class of compounds called antisense oligonucleotides may be used to target specific RNA sequences (splicing sites), thereby preventing them from directing production of 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,”

explained Dr. Raj.

“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. For example, we define the mechanism for three of the genetic variants 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,”

said Philip De Jager, MD, Ph.D., senior and co-corresponding author of the study and Director for the Center of Translational and Computational Neuro-Immunology at Columbia University.

Towfique Raj, Yang I. Li, Garrett Wong, Jack Humphrey, Minghui Wang, Satesh Ramdhani, Ying-Chih Wang, Bernard Ng, Ishaan Gupta, Vahram Haroutunian, Eric E. Schadt, Tracy Young-Pearse, Sara Mostafavi, Bin Zhang, Pamela Sklar, David A. Bennett & Philip L. De Jager
Integrative transcriptome analyses of the aging brain implicate altered splicing in Alzheimer’s disease susceptibility
Nature Genetics 08 October 2018

Image: A hairpin loop from a pre-mRNA. Highlighted are the nucleobases (green) and the ribose-phosphate backbone (blue). Note that this is a single strand of RNA that folds back upon itself. Credit: Vossman