Evidence suggests that alpha-synuclein can cause neuron death in Parkinson's disease (PD) by forming clusters (or aggregates) on the surface of small structures inside the cell called vesicles (storage packets). 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 those with PD, indicating that the death of neurons in PD may result in part from a loss of the protective action of ENSA against the harmful effects of alpha-synuclein.
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.
Viruses designed to produce elevated levels of alpha-synuclein will be injected with or without an ENSA-producing virus into the substantia nigra, a region of the brain that is associated with neuron loss in PD. In a second set of experiments, brain tissue from individuals with PD containing alpha-synuclein aggregates will be injected with or without an ENSA-producing virus into the substantia nigra. Models will be analyzed for evidence of motor abnormalities and tissues 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.
Next Steps for Development:
At the completion of this study, the next steps toward clinical application of our findings will be to screen for compounds that increase ENSA levels in the brain, stabilize the complex formed by ENSA and alpha-synuclein on vesicles or interfere with chemical modifications of ENSA that prevent its binding to alpha-synuclein.