Mechanism of Transposon Silencing in the Brain

/Abstract Transposable elements (TEs), first discovered by Barbara McClintock, are mobile DNA sequences that can relocate within the genome. Once dismissed as “junk” or “selfish” DNA, TEs are now recognized as contributors to both normal development and disease. TEs make up large portions of many genomes, yet their regulation—especially in somatic tissues like the brain—remains poorly understood. Retrotransposons, or Class I elements, mobilize through a copy-and-paste RNA intermediate and remain active in the human germline, brain, and cancers. Notably, retrotransposon activity in neurons can generate somatic mosaicism, contributing to neuronal diversity but also to genome instability. Elevated TE expression has been implicated in several neurodegenerative diseases, including ALS, FTLD, and Alzheimer's disease. In the germline, TEs are repressed by the piRNA pathway, but this system is largely absent in the brain, suggesting the existence of alternative silencing mechanisms. Our preliminary data have identified (a) a novel TE-silencing protein expressed in the adult brain, and (b) that TE loci in the brain are transcriptionally active, unlike in the ovary. We hypothesize that the brain employs distinct, tissue-specific mechanisms to post-transcriptionally silence TEs and preserve neuronal function. The long-term goal of this proposal is to uncover how neurons regulate transposon activity to maintain genome integrity and prevent neurodegeneration. In Aim 1, we will define the mechanism of a newly identified TE silencing protein in the brain. In Aim 2, we will identify and characterize the RNA-binding protein network that recognizes and suppresses TE mRNAs. These studies will provide new insight into brain-specific genome defense pathways and their relevance to neurological disease. Project Number: 1R21NS145053-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: VAMSI GANGARAJU | Institution: MEDICAL UNIVERSITY OF SOUTH CAROLINA, CHARLESTON, SC | Award Amount: $415,250 | Activity Code: R21 | Study Section: Molecular Neurogenetics Study Section[MNG] View on NIH RePORTER: https://reporter.nih.gov/project-details/11373883