Nigrostriatal Alpha-Synuclein Over-Expression in Young and Aged Pre-Clinical Models
Rapid Response Innovation Awards, 2012
Accurate pre-clinical models of Parkinsonís disease are needed in order to test novel therapies as well as to further our understanding of the disease itself. The molecule alpha-synuclein has been linked to many forms of Parkinsonís disease and overexpression of alpha-synuclein has been used to recapitulate key pathophysiological features of Parkinsonís disease. However, since aging is the primary risk factor for the development of Parkinsonís disease it is important to evaluate how the aged brain responds to alpha-synuclein overexpression. We hypothesize that overexpression of alpha-synuclein in the aged pre-clinical model brain will lead to a greater magnitude of degeneration than what occurs in the younger brain.
We have previously characterized the impact of alpha-synuclein overexpression in the young adult pre-clinical model on measures of motor impairment and degeneration of dopamine neurons. Viral vectors were used to deliver alpha-synuclein to the nigrostriatal system. In the present study, we propose to utilize identical alpha-synuclein viral vectors to overexpress alpha-synuclein in the aged pre-clincial model nigrostriatal system and to directly compare findings to results from young adult pre-clinical models.
Relevance to Diagnosis/Treatment of Parkinsonís Disease:
Neuroprotective strategies for the treatment of Parkinson's disease that have been tested in pre-clinical models have a poor track record in predicting clinical success. While part of this failure is likely due to our limited understanding of the causes of Parkinson's disease, another piece of the puzzle may be the fact that almost all preclinical studies fail to model the environment of the aging brain. We contend that the combined model of alpha-synuclein overexpression in the aged pre-clinical will more accurately model the parkinsonian brain. Characterization of this combined model is therefore of value to the research community.
If our hypothesis is substantiated and alpha-synuclein overexpression leads to amplified toxicity in the aging brain, then delineating the cause(s) of this increased toxicity may provide insight into the disease process itself. Follow up studies could start with the investigation of whether differences exist between alpha-synuclein infected young and aged pre-clinical models in levels of neuroinflammation and/or oxidative stress.
These studies have yielded two major findings. First, we have found that the aged brain is more susceptible to alpha-synuclein mediated toxicity than the young adult brain. Alpha-synuclein was the first gene discovered to be related to familial Parkinsonís disease (PD) and is a key constituent in the pathological hallmark in PD, Lewy bodies. The mechanisms governing this increased susceptibility of the aged brain to alpha-synuclein toxicity deserve further study and may provide information into why nigral dopamine neurons degenerate in PD and why aging is the primary risk factor for PD. Second, our results indicate that the aged brain is less amenable to gene therapy than the young adult brain. Since many gene therapy approaches currently under development are for use in diseases of aging, understanding why gene transfer is less efficient in the aged brain is an important next step.
Professor and Associate Chair at Michigan State University
Location: Grand Rapids, Michigan, United States