The eukaryotic stress response involves translational suppression of non-housekeeping proteins, and the sequestration of unnecessary mRNA transcripts into stress granules (SGs). This process is dependent on mRNA binding proteins (RBPs), such as T- cell intracellular antigen (TIA-1). RBPs interact with unnecessary mRNA transcripts through prion and poly-glutamine like domains, and their aggregation mirrors proteins linked to neurodegenerative diseases. Recent advances in molecular genetics emphasize the importance of SG biology in disease by associating multiple RBPs linked to SGs with neurodegenerative disease. The major difference between SG proteins and aggregation prone proteins in neurodegeneration is that aggregation of SGs is transient and rapidly reverses when the stress is removed. In contrast, aggregates associated with disease are stable and accumulate over time.
This study identifies overabundant SGs as a novel pathology in Alzheimer's disease and related tauopathies. The data suggest that TIA-1 is intimately linked to tau pathogenesis, acting as a modifier of tau aggregation and associated toxicity. TIA-1 is present in a protein complex with tau protein including hyper-phosphorylated and misfolded tau. The expression of WT or P301L mutant tau increases the formation and size of TIA-1 positive SGs, and the localization and dynamics of these SGs are altered. Conversely, the expression of TIA-1 increases the formation and stabilization of phospho- and misfolded tau inclusions, as well as visible alterations in microtubule morphology, perhaps reflecting a loss of tau function. The data further show that co-expression of TIA-1 and tau leads to dendrite shortening, increases in caspase cleavage, and apoptosis in primary neurons, suggesting that an interaction between TIA-1 and tau results in neurotoxicity. This toxicity is SG-dependent and is rescued by microtubule stabilizing drugs.
The results of this thesis research suggest that the aggregation of tau may proceed through the SG pathway, with SG formation accelerating the pathophysiology of tau aggregation. These studies propose that these tau aggregates serve as a nidus for further accelerated aggregation of SGs, leading to formation of long-lived pathological SG.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/16021 |
| Date | 08 April 2016 |
| Creators | Vanderweyde, Tara Elizabeth |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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