Sadaf Amin, Ph.D.

ABSTRACT

This study investigates a newly discovered link between innate immune signaling and the age-related decline of RNA splicing fidelity in the brain. The team’s preliminary data identify the antiviral DNA sensor cGAS as a previously unrecognized driver of neuronal splicing dysregulation: in a progranulin-deficient mouse model of accelerated brain aging, deleting cGAS restored splicing factor expression, rescued the vast majority of mis-splicing events, and reversed behavioral deficits. Using chronologically aged wild-type and cGAS-deficient mice (3 vs. 30 months), isoform-resolved single-nuclei transcriptomics, and interactome profiling in human cell models, the project will define cGAS-dependent splicing aberrations across the lifespan and determine whether cGAS regulates RNA processing through canonical interferon signaling or a direct, non-canonical mechanism. Because cGAS is a druggable target already in clinical development, the work could establish splicing fidelity as a reversible feature of molecular aging and open new therapeutic strategies for age-related cognitive decline. Findings will anchor planned NIH R01 and MIRA (R35) applications.
Lay Summary:
Aging is the greatest risk factor for cognitive decline and memory loss. As we age, brain cells gradually lose the ability to accurately process genetic information. One key process, RNA splicing, acts like an editor, ensuring the right proteins are made to support brain-cell function — and when it becomes faulty, brain function suffers. Why this breakdown happens with age has remained unclear.
Dr. Amin’s research points to an unexpected culprit: the immune system. A protein called cGAS, normally used by cells to detect infection, can become chronically active with age. In models of accelerated brain aging, removing cGAS restored normal RNA processing, revealing a direct link between immune activation and cellular decline. By studying young and old mice, as well as human cells under aging-related stress, the team will determine how immune signaling disrupts the RNA “editing” machinery over time. Because drugs targeting cGAS are already being developed, this work could point to new ways to preserve brain function and combat age-related decline.