RNA Processing in Aging-Associated Disease

Overview

RNA-binding proteins (RBPs) are critical post-transcriptional regulators that control mRNA processing, alternative splicing, stability, and translation. Mutations or mislocalization of RBPs are causally linked to neurodegenerative diseases including ALS (Amyotrophic Lateral Sclerosis), FTD (Frontotemporal Dementia), and Alzheimer’s disease and related dementias (ADRD). When key RBPs such as TDP-43 lose their normal function, mRNA splicing goes awry — leading to the inclusion of “cryptic exons” in mature transcripts, premature termination, and the production of aberrant RNA and protein species whose functional consequences have been poorly understood.

The lab studies the mechanisms by which RBP loss of function leads to aberrant RNA processing and how the resulting mis-spliced transcripts contribute to disease pathogenesis. A proteogenomic approach — combining long-read RNA sequencing with high-resolution mass spectrometry — is used to detect novel proteins translated from cryptic exon-containing transcripts in patient-derived models and post-mortem tissue. In parallel, the lab provides high-quality long-read transcriptomic resources to the community through the iPSC Neurodegenerative Disease Initiative (iNDI), a large collaborative effort with the NIH Center for Alzheimer’s and Related Dementias (CARD).