Study Rationale:
Evidence suggests that alpha-synuclein can cause cell death in the brains of those with Parkinson's disease (PD) by forming clusters (or aggregates) on the surface of small storage structures inside the cell called vesicles. We recently found that endosulfine-alpha (ENSA), a protein that binds to alpha-synuclein on vesicles, blocks the formation of alpha-synuclein aggregates on the vesicle surface and reduces the toxicity of alpha-synuclein to cultured neurons. ENSA levels are lower than normal in the brains of those with PD, indicating that cell death in PD may result in part from a loss of the protective action of ENSA against the harmful effects of alpha-synuclein.
Hypothesis:
This study addresses the hypothesis that ENSA can alleviate neuron death caused by the formation of alpha-synuclein aggregates in pre-clinical models of PD.
Study Design:
Viruses designed to increase levels of alpha-synuclein will be injected with or without a ENSA-producing virus into pre-clinical models targeting the substantia nigra, a brain region that is significantly affected by PD. In a second set of experiments, PD brain tissue samples containing alpha-synuclein aggregates will be injected with a virus with or without ENSA in the substantia nigra . Models will be analyzed for evidence of motor abnormalities and brain tissue will be examined to determine the degree of neuron loss and alpha-synuclein aggregate formation.
Impact on Diagnosis/Treatment of Parkinson's disease:
The results of our study will shed light on the ability of ENSA to reduce neurotoxicity resulting from alpha-synuclein aggregate formation or the spreading of alpha-synuclein aggregates throughout the brain. These insights will set the stage for developing PD therapies aimed at increasing the interaction of ENSA with alpha-synuclein in the brain.
Next Steps for Development:
At the completion of this study, the next steps toward clinical application of our findings include screening for compounds that increase ENSA levels in the brain, stabilizing the complex formed by ENSA and alpha-synuclein on vesicles or interfering with chemical modifications of ENSA that prevent its binding to alpha-synuclein.