Although Parkinson’s disease is mainly sporadic, at least six genes have been recently linked to familial PD. It is believed that a molecular understanding of the consequences of these gene mutations leading to nigral dopaminergic degeneration will help to devise new therapies for PD.
The aim of the present proposal is to screen promising small molecules on a genetic model of PD based on the lentiviral-mediated overexpression of alpha-synuclein (Lobianco et al. 2002). This model has been shown to recapitulate the main morphological features of PD, i.e., the death of nigral neurites and cell bodies.
The small molecules to be tested have been selected based on the current understanding of the pathophysiological mechanisms linked to the degeneration process. Arimoclomol (enhancing the chaperone-mediated refolding pathway) and rapamycin (stimulating the autophagic degradation pathway) have recently shown significant neuroprotective effects in animal models of amyotrophic lateral sclerosis and Huntington’s disease, respectively. Neither molecule has been evaluated in a genetic PD model.
Additionally, we propose to validate in our genetic pre-clinical model extra molecules (tocainide, FTI-277 and (+)-UH 232) identified from a genetic high-throughput screening performed on transgenic flies overexpressing alpha-synuclein. We believe that this approach can facilitate the discovery of new therapies for PD.
Final Outcome
While it was not possible to conclusively determine the efficacy of the proposed compounds, the project did result in the further development of the viral alpha-synuclein model. In particular, a new viral vector was established that enabled the researchers to reach conditions of alpha-synuclein overexpression leading to protein aggregation, mild neuronal degeneration and functional deficits monitored by behavioral testing. Using this model, the team is now in the process of thoroughly analyzing molecular and cellular perturbations of the nigrostriatal system in response to alpha-synuclein and implementing the testing of potentially neuroprotective genes and small molecules.
This work resulted in a publication in the journal Human Molecular Genetics and follow-on funding from the Swiss National Science Foundation.