Molecular Mechanisms of neurodegeneration & Structure-based drug design
Parkinson disease is a pathological condition of accelerated neurodegeneration. Specifically, the neurons (brain cells) in the substantia nigra pars compacta die at unusually rapid rate. By the time symptoms are visible, usually hand tremors, about 70% of neurons in this part of the brain is already death.
The focus of our research group is to uncover the molecular pathways leading to the disease state and to design drugs that would block these pathways. To do this, we are examining the biochemical and biophysical properties of the proteins in these pathways to piece them together like assembling a puzzle and to use each piece of the puzzle as a framework to design drugs that block them from interlocking with each other.
We hope that what we uncover about Parkinson disease will be useful in understanding other neurodegenerative diseases (such as Alzheimer disease and ALS) and the natural process of brain decline as we age.
1) Structure and function of α-Synuclein (aSyn). Aggregation of aSyn leading to formation of Lewy bodies is a pathophysiological hallmark of PD. The function of aSyn and how it forms Lewy bodies was unclear, but the prevailing model was that aSyn is a natively unfolded protein. As such, it could easily misfold into aggregation prone species that then goes on to aggregate into Lewy bodies. However, in our effort to prepare samples suitable for determining the structure of aSyn using X-ray crystallography, we found that aSyn is in fact not natively unfolded, but instead it forms a stably folded tetramer. We are now focusing on determining the crystal structure of aSyn to understand the structural bases for Lewy body formation.
2) Role of inflammation in the pathogenesis of Parkinson’s disease. We recently found that activating the inflammation pathways with various chemical agents led to proteolytic cleavage of aSyn and rendering it aggregation prone in vitro and in vivo. We are now investigating the molecular consequences of aSyn under these inflamed conditions in neurons to better understanding the toxic species and disease pathways. We are also testing whether inhibiting inflammation could be an effective therapeutic strategy.
3) Structure and function of LRRK2. Mutation in Leucine Rich Repeat Kinase 2 (LRRK2) is a common cause of PD. LRRK2 is a large multi-domain protein whose function is unknown. It is an attractive drug target because it consists of enzymatic domains, which consist of pockets into which we can fit drug molecules – because of that virtually every major drug company has a LRRK2 project. However, the mechanism of LRRK2 in disease pathogenesis is completely unknown. A prevailing model was that LRRK2 dimerizes via its GTPase domain (Roc) or via a domain C-terminal of Roc (Cor) and that this dimerization is necessary for its GTPase activity. However, we found that Roc in its monomeric form is equally active compared to the dimeric form. We further determined that a disease-associated mutation R1441H pathologically locks the Roc domain in a persistently active state.
We are now focusing on understanding the mechanism of R1441H in modulating Roc activity by determining its atomic structures using X-ray crystallography. We will use this information to develop compounds that could reverse the effects caused by disease-associated mutations, which we hope would further develop into effective drugs to combat this devastating disease.