A Potential Role for TLR9 Dysfunction in the Pathogenesis and Progression of Repeat Expansion Disorders

Abstract

Expansions of unstable DNA repeats in the human genome give rise to neurological disorders, but the mechanisms linking high numbers of DNA repeats to disease pathogenesis are not completely understood. The innate immunoreceptor toll-like receptor 9 (TLR9) is an endosomal DNA detector that responds to unmethylated CpG motifs and triggers adaptive immune responses and neurodegenerative changes. Human CpGs are normally methylated, but methylation declines with aging, a change that is correlated with increased risk of symptoms in repeat expansion disorders. In this thesis, I investigated the possibility that disease-associated DNA repeats that contain or generate de novo CpG motifs could dysregulate TLR9 signaling and drive neurodegeneration. To begin to explore this hypothesis, I calculated Risk Factor 3 (RF3) values for disease-associated DNA repeats. RF3 is a value that estimates predicted TLR9 responses to a given DNA sequence by differentially weighting known TLR9 -inhibitory and -excitatory motifs. Examination of DNA repeats associated with different disorders revealed that three of these repeats (seen in Oculopharyngeal Muscular Dystrophy (OPMD), some forms of Fragile X Syndrome (FRX), and Myoclonic Epilepsy (EPM1)) contain one or more existing CpG motifs, while two repeats (seen in Amyotrophic Lateral Sclerosis (ALS)/Frontotemporal Dementia (FTD) and other forms of Fragile X Syndrome (FRX) create de novo CpGs bridging individual repeats. All repeats that contain new or existing CpGs have a significant, dose-dependent effect on predicted TLR9 responses. For the first time, a potential role for TLR9 dysfunction in the pathogenesis and progression of DNA repeat expansion disorders is outlined and the potential therapeutic utility of immunomodulatory approaches is suggested.