Objective/Rationale:
Drugs for treating Parkinson's disease have to date been identified by trial and error. We are using protein structure as a guide for identifying potential drug targets for treatment of PD. In particular, we are interested in the role of α-synuclein clusters in PD progression, and we will determine whether these clusters are suitable targets for rational drug design.
Project Description:
The protein α-synuclein (αS) is a major component of Lewy bodies, aggregates of mis-folded proteins that are characteristic of PD. Under normal conditions, αS is soluble and is found abundantly in presynaptic terminals of dopaminergic neurons. We are trying to understand the reasons behind the transition between the soluble (normal) and insoluble (PD-related) forms of αS. We are using structural nuclear magnetic resonance (NMR) methods to determine whether clusters of four αS molecules (tetramers) stabilize αS against formation of insoluble αS aggregates that lead to Lewy bodies. The existence of such tetramers was proposed based on results from work in the laboratory of our collaborators, who cloned the αS gene and expressed the αS protein in bacteria. Multidimensional NMR, selective and uniform isotope labeling and isotope-edited NMR will be used to distinguish between monomer units in the tetramer. Once we have determined the structure of the tetramer, we will use rational design and template matching to search for drug leads that stabilize the soluble tetramer form of the protein.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The role of αS in normal dopaminergic neuron function is still unclear. However, the insoluble form of αS clearly plays a role in the progression of PD, accumulating in Lewy bodies that are diagonstic of PD. If we can learn how to stabilize the soluble form of αS, we open the door to a new class of drugs for slowing (or even reversing) the progression of PD.
Anticipated Outcome:
By the end of this year-long project, we anticipate that we will know the structure of the αS tetramer, and we will have begun screening the binding of small molecule drug leads to the tetramer structure.
Final Outcome
The protein alpha-synuclein is a major component of insoluble amyloid aggregates (called Lewy bodies) found in nerve tissues that are affected by Parkinson's disease. A novel preparation method for alpha-synuclein has resulted in the identification of a soluble oligomeric form that may be the immediate precursor for amyloid formation. Nuclear magnetic resonance methods are being used to determine the structure of this oligomer as a guide to the development of drugs that will stabilize the oligomer and slow or prevent precipitation of amyloid.