Study Rationale:
Current therapeutic strategies against synucleinopathies aim to either stabilize a native form of alpha-synuclein or to reduce its levels in patients. However, the normal physiological structure and function of alpha-synuclein are still not understood in the protein’s local environment. This knowledge is essential to understand the role of alpha-synuclein in health and disease and to assess the short- and long-term consequences of modulating alpha-synuclein levels in patients.
Hypothesis:
With the work proposed here we hope to 1), define the native states of alpha-synuclein at the pre-synapse toward which therapeutic strategies might be targeted in the future; 2), elucidate the sequence, molecular and cellular determinants of alpha-synuclein function in health and disease; and 3), determine the consequences on modulating alpha-synuclein levels in health and disease.
Study Design:
We will apply high-resolution biophysicial and imaging techniques, including different specific antibodies against all different variants of alpha-synuclein, to characterize the localization of alpha-synuclein at the synapse under normal physiological function of the neuron.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
The proposed studies will provide new potential target structures; novel insight into the molecular, structural and cellular determinants of alpha-synuclein function; and an understanding of disease-associated mutations and modifications.
Next Steps for Development:
It is possible that some of the discovered conformations can be stabilized by small molecules and that native state stabilization turns out to be a viable future strategy against disease.