Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

First Advisor

Guo, Junjie

Abstract

A nucleotide repeat expansion (NRE) (GGGGCC)n in the first annotated intron of the C9ORF72 (C9) gene is a common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While previous studies have shown that C9 NRE produces several toxic dipeptide repeat (DPR) proteins, how an intronic RNA segment can access the cytoplasmic translation machinery remains unclear. By capturing and sequencing NRE-containing RNAs from patient-derived fibroblasts and neurons, I found that C9 NRE became part of an alternatively spliced exon 1 through the usage of various downstream 5ʹ splice sites. These NRE-containing splice isoforms accumulate in C9 ALS/FTD brains, and their production is promoted by serine/arginine-rich splicing factor 1 (SRSF1). Antisense oligonucleotides targeting either SRSF1 or C9 NRE-containing splice isoforms reduced DPR levels. Together, my findings revealed a crucial role of aberrant splicing in the biogenesis of NRE-containing RNAs and demonstrated potential therapeutic strategies to target these pathogenic transcripts.

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