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Dissertation/Thesis Abstract

Characterization of the Transcriptional, Proteomic, and Oxidative Stress Profile in Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) Brain
by Holm, Katharine Nichole, Ph.D., University of California, Davis, 2020, 137; 28095655
Abstract (Summary)

Age-related neurodegenerative diseases are among the leading causes of death in the U.S. population aged 65 years or older. The complex relationship between aging, disease progression, genetic risk, and environment in neurodegenerative diseases remains incompletely understood. One such age-related neurodegenerative disease is Fragile X-associated tremor/ataxia syndrome (FXTAS), which is caused by a premutation (PM) range expansion (50-200 repeats) of the trinucleotide CGG repeat element in the 5’ untranslated region of the FMR1 gene. In spite of detailed, organelle-specific characterization of cellular dysfunction in FXTAS, the complete cellular profile and mechanism of disease has yet to be identified. This study represents the first known large-scale proteomic and transcriptomic profile of end-stage FXTAS in human brain. It is also the first known large-scale effort to characterize oxidative stress in FXTAS patient-derived brain and fibroblasts. We found differential abundance and expression of a number of novel protein and mRNA species in FXTAS, unique to FXTAS when compared to other neurodegenerative diseases. Contrary to previous models and evidence in other neurodegenerative diseases, we did not identify significant differences in oxidative stress, therefore suggesting a limited contribution of this pathway to disease progression. Overall, these findings suggest end-stage FXTAS is a complex disease presenting with a unique, heterogenous profile of affected pathways. Further research into these pathways may yield insight into the initiating events of FXTAS disease onset and progression.

Indexing (document details)
Advisor: Hagerman, Paul J.
Commitee: Nord, Alex, Tassone, Flora
School: University of California, Davis
Department: Genetics
School Location: United States -- California
Source: DAI-B 82/8(E), Dissertation Abstracts International
Subjects: Genetics, Neurosciences, Aging
Keywords: Fragile X-associated Tremor/Ataxia Syndrome, Oxidative stress, Proteome, RNA Binding Motif 3, Tenascin-C, Transcriptome
Publication Number: 28095655
ISBN: 9798582531173
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