Determining the Role of Glucose Hypometabolism as a Modifier of C9orf72-ALS/FTD: Potential Mechanisms and Downstream Consequences
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two progressive neurodegenerative diseases characterized by the loss of motor neurons and/or cortical neurons, leading to motor dysfunction, cognitive decline, and ultimately death. The most prevalent genetic cause of both ALS and FTD is a GGGGCCn repeat expansion mutation occurring in a noncoding region of the C9orf72 gene. The mutation undergoes an aberrant, non-canonical form of protein translation – referred to as repeat-associated non-ATG (RAN) translation – leading to the production of dipeptide repeat proteins (DPRs), which are toxic to neurons and are thought to be a primary driver of neurodegeneration. However, the mechanistic details and precise cellular consequences of RAN translation and DPR accumulation are not fully established, which is partly due to technical limitations in detecting and quantifying DPR levels. In this thesis document, we explore these aspects of RAN translation. In particular, we demonstrate that glucose hypometabolism – which is an early and consistent phenomenon in carriers of the C9orf72 mutation – can act as a molecular trigger or modifier of RAN translation and DPR accumulation within neurons, specifically through activation of the integrated stress response (ISR) pathway. We also uncover and characterize several toxic mechanisms through which the arginine-rich DPRs can cause cellular dysfunction and toxicity, also within neurons. And finally, we also describe the development and optimization of a novel single-molecule array (Simoa) immunoassay that enables highly sensitive detection of DPRs in both patient samples and preclinical model systems. Overall, our findings indicate a destructive feedforward loop that could be initiated by glucose hypometabolism, leading to increased DPR production, in turn enhancing the level of neurodegeneration and cellular stress and further exacerbating DPR production.
Subject Area
Neurosciences|Cellular biology|Genetics
Recommended Citation
Nelson, Andrew Tyler, "Determining the Role of Glucose Hypometabolism as a Modifier of C9orf72-ALS/FTD: Potential Mechanisms and Downstream Consequences" (2023). ProQuest ETD Collection - Thomas Jefferson University. AAI30485196.
https://jdc.jefferson.edu/dissertations/AAI30485196
