Structural studies on mechanisms of prion-like protein assemblies

Degenerative diseases of the brain such as Alzheimer’s, Parkinson’s and prion diseases are associated with build-up of aggregates of misshapen protein molecules in the brain. We want to understand how these aggregates form and how they cause damage to brain cells. To understand these processes at a molecular level we use a range of techniques including a special type of electron microscopy (Cryo-EM). The protein aggregates in several degenerative brain diseases can self-propagate and spread from cell-to-cell like prions (that cause the human disease CJD) and exist as distinct sub-types or strains. Alzheimer's disease (AD) is the most common neurodegenerative disease and accumulation of aggregates of Amyloid-beta (Abeta) is believed to be necessary for the initiation of AD. We are trying to resolve the atomic structures of the Abeta protein aggregates from different subtypes of AD by Cryo-EM, and study how are they regulated and how they cause damage to the brain. Similar mechanisms of protein aggregation can also be studied in yeast models and we will also study similar questions on yeast prions and uncover their relevance to the human prion-like proteins. Ultimately, we hope this will help in design of diagnostic tools and therapeutics for neurodegenerative diseases.