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Open Access Publications from the University of California

Structural Studies of Pathogenic Amyloids

  • Author(s): Sangwan, Smriti
  • Advisor(s): Eisenberg, David
  • et al.

My research project is focused on deciphering the structural basis of toxicity in neurodegenerative diseases including Parkinson’s and Lou Gehrig’s (ALS) disease. Even though large proteinacious deposits that are amyloid in nature are found in these diseases, scientific evidence in recent years has tilted the opinion in favor of small oligomers as the more toxic species. However, the transient nature of these small oligomers has made their study extremely difficult. The Eisenberg lab has focused on characterizing amyloid aggregates from a structural perspective. We have deciphered the atomic resolution structure of segments from these proteins in their amyloid-like conformation and used the structures to design inhibitors that prevent aggregation. We have now focused on characterizing these transient oligomers. In my research, I have worked on two amyloid-forming proteins namely Superoxide Dismutase 1 (SOD1) and Alpha Synuclein (α-syn) and have attempted to understand the basis of their toxicity. My results suggest two different modes of action for these proteins. For SOD1, moderately sized oligomers

seem to be more toxic than insoluble amyloid aggregates, but for α-syn the fibers are more toxic. Using the atomic structure of the spine of α-syn fibrils, I have developed a new line of inhibitors that prevent fibril growth and propagation. My results reveal a novel therapeutic approach targeted at the spread and progression that may be applicable for PD and related synucleinopathies.

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