A reliable, characterized and validated model of synucleinopathies (disorders in which there is an excessive accumulation of the protein alpha-synuclein) would provide a critical tool with which to study the pathophysiology of Parkinson's disease (PD) and test potential neuroprotective therapies. Synucleinopathy induced in neurons by sonicated (applying sound waves) preformed alpha-synuclein fibrils (protein clumps) holds great potential to provide such a model.
The studies performed in this project will examine pre-clinical models of alpha-synuclein and the subsequent ability of these preformed alpha-synuclein fibrils to seed accumulation of phosphorylated (modified) alpha-synuclein. It is hypothesized that alpha-synuclein in pre-clinical models can form fibrils and that sonicated forms of these preformed fibrils will create alpha-synuclein bundles.
Different types of alpha-synuclein will be exposed to conditions known to generate the fibrillar species. The fibrillar structure of both types will be validated by many outcome measures and ultimately applied to neurons in cell culture and injected into the striatum to determine whether endogenous clumps accumulate.
Impact on Diagnosis/Treatment of Parkinson's disease:
This research will determine whether preformed fibrils of alpha-synuclein in pre-clinical models will produce clumping in neurons. This research also will provide quality control for different batches of alpha-synuclein prior to distribution to the broader research community.
Next Steps for Development:
Future studies could examine whether preformed fibrils generated from alpha-synuclein could provide the ideal fibril species for generation of synucleinopathies, thus leading to a break down of motor pathways in the brain.