Tau-Induced Elevation of the Activity-Regulated Cytoskeleton Associated Protein Arc1 Causally Mediates Neurodegeneration in the Adult Drosophila Brain

• Main Author: Schulz, Cynthia Lu
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01.01.2022
• Subjects: Cellular biology; Molecular biology; Neurosciences
• ISBN: 9798834032724

Tauopathies are a group of neurodegenerative diseases defined by the pathological aggregation of hyperphosphorylated tau into toxic tau oligomers. Accumulation of pathogenic tau initiates a cascade of downstream cellular consequences, including actin overstabilization, heterochromatin relaxation, aberrant gene expression, and transposable element activation, which ultimately lead towards neuronal death. One of the first cellular events in tau-induced neurodegeneration is synaptic dysfunction, and is most closely associated with cognitive decline and dementia. Synapses are complex structures that form the physical basis of learning and memory, and thus require dynamic changes in gene expression and protein interactions to respond to changes in neural activity. The activity regulated cytoskeleton associated protein ARC serves as a master regulator of various forms of synaptic plasticity and memory formation. Interestingly, ARC protein contains a retrovirus-like Group specific antigen (Gag) domain that facilitates assembly into multimeric capsids that traffic RNA across synapses within extracellular vesicles. Recent evidence from our lab indicates that Arc1 mRNA is significantly elevated in adult tau transgenic Drosophila melanogaster as a result of tau-induced defects in nonsense mediated mRNA decay (NMD). Although it is well established that ARC is required for maintenance of synaptic plasticity and memory, it is currently unknown if tau-induced Arc1 elevation drives neurotoxicity. I have utilized classical biochemistry and histological techniques and established neurotoxicity readouts in a Drosophila model of tauopathy to discover that pathogenic tau-induced Arc1 overexpression causally mediates neurodegeneration. I find that the tau-induced increase in Arc1 transcripts increases multimeric Arc1 protein species and that Arc1 protein levels are increased in the neuropil and nucleus in brains of tau transgenic Drosophila. Mechanistically, I identify Arc1 as a genetic modifier of tau-induced neurotoxicity and subsequent neuronal death. This study provides meaningful evidence for the connection between synaptic plasticity and tau-induced neurodegeneration and lays the foundation for further investigation into how viruses domesticated in the human genome can negatively alter cellular mechanisms in the context of pathogenic tau.