The misfolding and aggregation of the protein alpha-synuclein has been identified as pivotal event causing Parkinson's disease. All cells in our body possess so-called chaperones that safeguard against protein misfolding. Nevertheless, their safeguarding capacity is apparently not enough to protect against Parkinson disease. Increasing cellular chaperone activity may stop or prevent Parkinson's disease. Here, we examine the potency of key chaperone systems and their mode of action to provide the basis for therapeutic efforts aimed at using chaperones.
The present proposal examines the mode of interaction of alpha-synuclein with pertinent cellular chaperones to assess the potency of different chaperone systems in preventing alpha-synuclein aggregation. This entails the examination of regions within alpha-synuclein that preferentially binding to chaperones, thus identifying them as problematic. The biophysical techniques of solution NMR spectroscopy, as well as fluorescence spectroscopy are used as main experimental tools. NMR can examine the interaction of individual amino acids of alpha-synuclein with chaperones present. Fluorescence spectroscopy is applied to assay the rate of misfolding of alpha-synuclein in the presence and absence of chaperones as well as control proteins to compare the efficiency of the studied chaperone systems. In addition, fluorescence spectroscopy can differentiate alpha-synuclein misfolding intermediates. Aside from the overall rate of alpha-synuclein misfolding, the population of certain intermediates appears particularly problematic in Parkinson's disease.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The increase of chaperone production by drugs has been shown in the literature. Upregulation of cellular chaperone production may hold therapeutic potential for treating Parkinson's disease. Furthermore, chemical compounds mimicking the mode of chaperone action hold promise to act directly as drugs that can assist cellular chaperones. To develop such drugs an understanding of the biophysical events underlying chaperone function is desirable. Thus, our projects holds potential to treat the events that initiate the Parkinson's disease process.
The potency of key chaperone systems of nerve cells is compared, thus identifying the most promising and most efficient chaperone system to use for therapeutic efforts. Furthermore, the mode of action of chaperone systems can assist drug development efforts aimed at reproducing these systems. Finally, our research will aid in answering the question whether drugs should be used/developed that upregulate cellular production of chaperones to resolve the misfolding of alpha-synuclein, which is at the core of Parkinson's disease.