Promising Outcomes of Original Grant:
We have successfully characterized the time course and magnitude of alpha-synuclein aggregation and neurodegeneration of the nigrostriatal system following optimized intrastriatal unilateral injection of preformed alpha-synuclein fibrils into pre-clinical models. We also observed a distinct interval of contralateral nigrostriatal degeneration as well as identified a pattern of inflammatory cytokine expression in cerebrospinal fluid (CSF).
Objectives for Supplemental Investigation:
In this supplemental project we will test the hypothesis that contralateral nigral degeneration is induced by excitotoxic mechanisms. We will also validate our previous results by examining the effect of PFF-triggered synucleinopathy on inflammatory cytokines in the CSF and plasma.
Importance of This Research for the Development of a New PD Therapy:
We believe understanding the mechanism of contralateral degeneration in this model to be important in order to be interpret the effect of potential neuroprotective therapies. It is also possible that the mechanism of contralateral degeneration, perhaps dependent upon an imbalance in dopamine, may represent a pathophysiological mechanism that is common to multiple forms of sporadic PD. Lastly, we believe that identification of a CSF inflammatory signal, prior to degeneration, could provide an important biomarker of early PD.