Date of Award

2014

Document Type

Restricted Thesis

Terms of Use

© 2014 Kathryn M. Wu. All rights reserved. Access to this work is restricted to users within the Swarthmore College network and may only be used for non-commercial, educational, and research purposes. Sharing with users outside of the Swarthmore College network is expressly prohibited. For all other uses, including reproduction and distribution, please contact the copyright holder.

Degree Name

Bachelor of Arts

Department

Biology

First Advisor

Bradley Justin Davidson

Abstract

Amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD) are fatal neurodegenerative diseases with overlapping genetic etiologies, pathological characteristics, and clinical symptoms. The most common associated genotype of both ALS and FTD is a GGGGCC repeat expansion in the C90RF72 gene. Central pathological hallmarks of C90RF72-associated disease are C90RF72 repeat-containing RNA foci and repeat-associated non-ATG- translated (RAN) protein products, which are hypothesized to contribute to neurodegeneration. The C90RF72 repeat expansion is also associated with lower C90RF72 transcript levels. We hypothesized that methylation within the C90RF72 promoter is involved in transcriptionally silencing expanded C90RF72 as a protective mechanism of reducing toxic C90RF72 products. Using a quantitative methylation-sensitive restriction enzyme assay, we measured promoter methylation in lymphoblasts as well as brain and spinal cord tissue from expansion carriers and controls. We found that promoter methylation correlates tightly with decreased C90RF72 RNA transcripts and is variably associated with the C90RF72 repeat expansion. Within expansion carriers, regions that typically experience heavy neuron loss had higher levels of promoter methylation than unaffected regions. This potentially reflects the selective retention of neurons with promoter methylation. Finally, promoter methylation correlated with increased disease duration and age of death within FTO patients. Taken together, our data supports a protective role for promoter methylation in C90RF72 expansion carriers.

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