ELAVL3 Cryptic Exon Inclusion and Pathological TDP-43 in ALS/FTD Open Access

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which causes the degeneration of both upper and lower motor neurons and leads to progressive muscle weakness. Approximately 5-50% of patients with ALS are also diagnosed with frontotemporal dementia (FTD), a form of dementia which leads to poor decision-making and altered personality characteristics. The most common genetic form of this comorbidity, C9orf72-linked ALS/FTD, has been previously found to contain TDP-43 pathology in the majority of patient cases. TDP-43, an RNA-binding protein integral to RNA processing, was found to have a loss-of-function and a gain-of-toxicity due to its mislocalization, hyper-phosphorylation, and perinuclear aggregation. Previous data from the Bassell lab found that the loss of cellular TDP-43 leads to RNA misprocessing events and identified the presence of cryptic exons in the ELAVL3 gene. Thus, this thesis aimed to examine the relationship between TDP-43 pathology and ELAVL3 cryptic exons, with the hypothesis that a cytoplasmic aggregation of TDP-43 leads to the inclusion of ELAVL3 cryptic exons in mRNA transcripts as a result of alternative splicing events. Among results, we found that the knockdown of TDP-43 in iPS-derived motor neurons leads to the inclusion of cryptic exons, TDP-43 pathology is present in hippocampal FTD patient tissue with ELAVL3 cryptic exons present, and the expression of ELAVL3 cryptic exons in patient tissue samples is correlated with high phosphorylated TDP-43 pathology. These results present novel evidence of the mechanisms behind ELAVL3 cryptic exon presence in ALS/FTD, as well as insight into the relationship between TDP-43 pathology and ELAVL3 cryptic exon occurrence in TDP-43 proteinopathies. 

Table of Contents

Introduction………………………………………………………………………………………..1

Methods……………………………………………………………………………………...……..7

Results……………………………………………………………………………………………...10

Discussion………………………………………………………………………………………....13

Future Directions………………………………………………………………………………...18

Figures………………………………………………………………………………………...……20

            Fig. 1…………………………………………………………………………………...…..20

            Fig. 2…………………………………………………………………………………...…..21

            Fig. 3………………………………………………………………………………….....…22

            Fig. 4…………………………………………………………………………………....….23

            Table 1………………………………………………………………………………..…...23

            Fig. 5…………………………………………………………………………………….....24

References…………………………………………………………………………………….…..25

About this Honors Thesis

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School	Emory College
Department	Neuroscience and Behavioral Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Neuroscience
Keyword	ALS Cryptic Exon TDP-43 FTD Splicing Neurodegenerative
Committee Chair / Thesis Advisor	Bassell, Gary, Emory University
Committee Members	McEachin, Zachary, Emory University Corbett, Anita, Emory University

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