Previously unknown genetic aberrations found to be associated with Alzheimer’s progression
Researchers present comprehensive genome-wide map of RNA splicing variation in aging brain – novel insights could offer new strategies for diagnosis and treatment of Alzheimer’s disease
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 have identified specific RNA splicing events associated with Alzheimer’s disease progression. In their study, published in October 2018 in Nature Genetics, the researchers present 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, PhD, Assistant Professor in the Ronald M. Loeb Center for Alzheimer's Disease, Departments of Neuroscience and Genetics and Genomic Sciences at Mount Sinai.
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, explained Dr. Raj. “This class of drugs shows promise in treating an array of brain disorders including spinal muscular atrophy, ALS, and Huntington’s disease.”
“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,” said Philip De Jager, MD, PhD, senior and co-corresponding author of the study 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 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.”
About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest integrated delivery system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai's vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The Health System includes approximately 7,480 primary and specialty care physicians; 11 joint-venture ambulatory surgery centers; more than 410 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools", aligned with a U.S. News & World Report's "Honor Roll" Hospital, No. 12 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 18 on U.S. News & World Report's "Honor Roll" of top U.S. hospitals; it is one of the nation's top 20 hospitals in Cardiology/Heart Surgery, Gastroenterology/GI Surgery, Geriatrics, Nephrology, and Neurology/Neurosurgery, and in the top 50 in six other specialties in the 2018-2019 "Best Hospitals" issue. Mount Sinai's Kravis Children's Hospital also is ranked nationally in five out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 11th nationally for Ophthalmology and 44th for Ear, Nose, and Throat. Mount Sinai Beth Israel, Mount Sinai St. Luke's, Mount Sinai West, and South Nassau Communities Hospital are ranked regionally.