Understanding the Consequences of Dipeptide Repeat Protein Formation in C9orf72-Als/Ftd
Dipeptide repeat protein (DPR) formation is one gain-of-function consequence of the hexanucleotide GGGGCC expansion associated with chromosome 9, open reading frame 72 amyotrophic lateral sclerosis and frontotemporal dementia (C9orf72-ALS/FTD). The C9orf72 mutation is the most common cause of ALS and FTD of known genetic origin. Five types of DPRs, poly- glycine-alanine (GA), glycine-arginine (GR), proline-alanine (PA), proline-arginine (PR), and glycine-proline (GP) are translated from repeat-rich RNA in a non-canonical method of translation called repeat-associated non-AUG (RAN) translation. These DPRs are diverse, varying in repeat length and toxicity profile. Specifically, arginine containing DPRs are among the most toxic species. However, there is much to learn about the consequences of DPR toxicity both independently and within a broader disease context. In this thesis, I explore the consequences of DPR expression independent of other C9orf72-linked loss- or gain-of-function disease mechanisms. I present studies that investigate 1) the consequences of expression of a single DPR of one length in in vitro and in vivo model systems, 2) the sub-cellular consequences of expressing a single DPR of one length, and 3) whether these consequences can be modulated with additional layers of stress. I demonstrate a pathogenic role for a short-length DPR in a variety of model systems, including a novel mouse model expressing this DPR under a ubiquitous promoter system. I identify histopathological, behavioral, and functional consequences in this DPR-expressing rodent model that suggests a chronic, non-progressive, and in some instances sex-specific, phenotype. I then explore the subcellular consequences of expression of this DPR, revealing co-localization with known phase-separating and/or aggregating proteins, including one associated with the nuclear pore complex. I end by exploring how DPR toxicity is altered in the presence of other disease-modifying stressors associated with C9orf72-ALS/FTD, identifying a role for glutamate elevation in modulating the consequences of DPR expression. Together, these studies aid in our knowledge of DPRs as more than simply disease biomarkers, strengthening the understanding that their toxicity is a contributor to C9orf72-ALS/FTD as part of a vast and complex disease mechanism.
Verdone, Brandie Morris, "Understanding the Consequences of Dipeptide Repeat Protein Formation in C9orf72-Als/Ftd" (2021). ETD Collection for Thomas Jefferson University. AAI28962246.