Study Rationale:
Pre-clinical models of Parkinson's disease (PD) can provide clues to disease mechanisms and serve as a platform to test novel treatment strategies. We have previously established that intra-striatal (brain region associated with PD) injection of preformed alpha-synuclein fibrils can result in pathology and loss of nigrostriatal dopamine. This proposal outlines steps to optimize this alpha-synuclein preformed fibril PD model.
Hypothesis:
We hypothesize that by using optimized surgical parameters we can establish a pre-clinical preformed alpha-synuclein PD model that will result in damage to approximately 75% of nigrostriatal dopamine neurons and consistently measurable behavioral impairments.
Study Design:
We will test the effects of varying the amount and distribution of preformed alpha-synuclein on the survival of nigrostriatal dopamine neurons and motor performance.
Impact on Diagnosis/Treatment of Parkinson's Disease:
The alpha-synuclein preformed fibril model could facilitate pre-clinical assessment of novel disease-modifying therapies.
Next Steps for Development:
Following successful optimization, external validation studies could be conducted in the alpha-synuclein preformed fibril model to make direct comparisons to clinical metrics used in the assessment of PD (e.g., levodopa responsiveness, longitudinal imaging studies).