PROJECT SUMMARY/ ABSTRACT
Many incurable neurodegenerative diseases including Alzheimer's, Parkinson's, and Huntingtin's feature the
presence of toxic misfolded proteins. These insoluble protein aggregates, amyloid fibrils (AF), have been
extensively studied and structural characterization has shown that they are largely composed of ß-sheets and an
ordered cross-ß fibril core; however, they are often framed by intrinsically disordered domains (IDDs) in the N
and C-terminal. Adding to the complex nature of AFs is the finding that many of them, including a-synuclein
(a-syn), amyloid-ß, and tau, are found as polymorphs. Polymorphism, in this context, enables a protein to fold
and self-propagate into different AF structures often accompanied by varying neuropathology. The high
flexibility of the IDDs has made it difficult to take their molecular picture thus limiting our understanding of how
they affect AF properties in disease. Recent studies have demonstrated the importance of studying the IDDs of
AF as they have been found to play an important role in mediating fibril toxicity, aggregation, and interactions
with cellular components. a-Syn is natively found as a soluble intrinsically disordered protein (IDP), but in
Parkinson's disease it misfolds and aggregates into AF found in Lewy bodies. The importance of a-syn in disease
context has resulted in numerous studies of its monomeric and fibrillar form, thus the fibril core of a-syn is well-
characterized and there are several high-resolution structures available including at least four polymorph
structures. This makes a-syn an ideal candidate to determine the differences in structure and dynamics of the
IDDs in the monomeric and fibrillar state and between polymorphs. To accomplish this, I will use solid-state
nuclear magnetic resonance and electron paramagnetic resonance spectroscopy in combination with molecular
dynamics simulations to develop two full-length a-syn models that will describe the dynamic and structural
properties of IDDs in fibrils and it will provide insight on the effects of polymorphism on the IDDs. In addition,
polymorphs will be tested for toxicity in a neural cell culture model. This research will provide fundamental
understanding of AF that can help future studies that focus on understanding how IDDs mediate toxicity, fiber-
cell interactions, and seeding properties.
