Date of Award
2024
Degree Type
Dissertation
Degree Name
Doctor of Philosophy in Biological and Environmental Sciences
Specialization
Cell and Molecular Biology
Department
Cell & Molecular Biology
First Advisor
Claudia Fallini
Abstract
Neurodegenerative disorders affect millions of people worldwide and are only expected to increase in prevalence as the world’s population ages. The progressive loss of neurons, their structure, and function can lead to detrimental effects as neurons are responsible for the integration of signals in the brain and spinal cord. Despite the association of genetic mutations leading to neurodegeneration, the etiology of many of the disorders is unknown. Understanding how cellular pathologies affect different subsets of neurons is a major goal in the field of cell and molecular neuroscience. Similarly, understanding the mechanisms that may drive these pathologies is of interest as defining the mechanisms behind disease can lead to the derivation of therapeutic targets and may also help to clarify how one pathology can feedback to another. This dissertation contains four chapters. The first is a review which focuses on understanding several shared cellular pathologies in common neurodegenerative disorders such as AD, HD, MS, FTD, and ALS. The second focuses on studies performed investigating the differences in the onset of several pathologies in cortical vs. motor control and ALS/FTD C9ORF72 mutant neurons. The third chapter focuses on the elucidation of a mechanism behind impaired CREB pathway activation in C9ORF72 mutant cortical neurons. The fourth chapter investigates the consequences of CREB pathway dysfunction in C9ORF72 mutant cortical neurons. Overall, several cellular pathologies that influence neurodegeneration, and particularly ALS/FTD are investigated in this dissertation, as well as a mechanism behind dendritic pathology in particular, and the disease relevant consequences of this driving mechanism are outlined. These results help to clarify the onset of pathologies in vitro as well as shed light on several new avenues for potential therapeutics.
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Recommended Citation
Gregoire, Michelle Jean, "ALTERED TRANSCRIPTIONAL REGULATION IS AN EARLY DRIVER OF DISEASE IN AN IN VITRO MODEL OF C9ORF72 ALS/FTD" (2024). Open Access Dissertations. Paper 1687.
https://digitalcommons.uri.edu/oa_diss/1687