Elucidating the Mechanisms of Transthyretin Aggregation in Transthyretin Amyloidosis
Dasari, Anvesh K. R
Accumulation of insoluble aggregates (amyloids) is a characteristic feature of many neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Aggregation and deposition of Transthyretin (TTR) protein in tissues leads to transthyretin amyloidosis. Aggregation of wild-type (WT) TTR shown to affect the heart, causing senile systemic amyloidosis (SSA), while the two pathogenic mutants (V30M, and L55P) affect the peripheral nervous system. It is important to understand the misfolding/amyloid formation mechanism towards the development of therapeutic strategies. TTR is rich in the [beta]-sheet structure in which eight [beta]-strands are arranged in a [beta]-sandwich consisting of two [beta]-sheets (strands CBEF and DAGH). Previous solution NMR studies have shown that the amyloid precursor state of TTR is also rich in [beta]-sheets. Our solid-state NMR results indicated the presence of intact native-like [beta]-sheets in the amyloid state as well. But, the AB loop region appeared to be perturbed during the aggregation which could expose strand A for intermolecular associations. Solid-state NMR results of the mutant forms (V30M and L55P) also indicated the presence of native-like [beta]-sheets in the amyloid states but, with a distorted DA strand which further exposes strand A for more aggressive intermolecular interactions. We also reported the aggregation mechanism for early aggregates which are shown to be cytotoxic in the amyloid formation pathway. We also discovered that the hexamers of TTR are the building blocks of these early toxic aggregates.
Dasari, Anvesh K. R. (July 2018). Elucidating the Mechanisms of Transthyretin Aggregation in Transthyretin Amyloidosis (Doctoral Dissertation, East Carolina University). Retrieved from the Scholarship. (http://hdl.handle.net/10342/6987.)
Dasari, Anvesh K. R. Elucidating the Mechanisms of Transthyretin Aggregation in Transthyretin Amyloidosis. Doctoral Dissertation. East Carolina University, July 2018. The Scholarship. http://hdl.handle.net/10342/6987. February 18, 2020.
Dasari, Anvesh K. R, “Elucidating the Mechanisms of Transthyretin Aggregation in Transthyretin Amyloidosis” (Doctoral Dissertation., East Carolina University, July 2018).
Dasari, Anvesh K. R. Elucidating the Mechanisms of Transthyretin Aggregation in Transthyretin Amyloidosis [Doctoral Dissertation]. Greenville, NC: East Carolina University; July 2018.
East Carolina University