The Michael J. Fox Foundation’s development and distribution of novel alpha-synuclein viral vectors to study Parkinson's disease.
Elisia M. Clark*, Nicole K. Polinski*, Bradford Casey*, Tomas Björklund**, Fredric P. Manfredsson***, James Koprich****, Steve Marshall*****, Jamie Eberling*
Alpha synuclein (aSyn) plays an important role in Parkinson’s disease (PD) with pathological changes of the protein observed in PD patients and mutations/multiplications in the gene leading to PD. Commonly used rodent models overexpress wildtype and mutant forms of aSyn, and have been helpful in understanding molecular mechanisms and the role of aSyn in PD pathogenesis. However, the lack of comparable phenotypes makes it challenging to reproduce PD in animal models. Therefore, it is important to have preclinical tools that best suits the scientific questions we want to answer to further our understanding of aSyn biology to develop and evaluate potential therapies for targeting aSyn aggregation. The Michael J. Fox Foundation for Parkinson’s Research (MJFF) sponsors the development of resources for PD research and drug development communities that endeavors to provide researchers with easy access to rigorously validated preclinical tools for their studies. The MJFF preclinical tools portfolio currently includes novel viral vector tools that utilize human aSyn to serve as a platform for PD model development. Recently, MJFF developed a novel adeno-associated virus (AAV) vector that can be used to overexpress human wildtype (WT) aSyn in different species. Extensive validation of this viral vector six weeks post-intranigral injection in rat shows dose-dependent degeneration of the nigrostriatal system and corresponding motor impairments, producing an ideal platform for studying PD biology and therapeutic interventions. We also showcase data from an MJFF-generated virus that overexpresses the A53T mutant form of aSyn, including behavioral deficits and nigrostriatal degeneration at 6 weeks post-intranigral injection in rat. Finally, we highlight a different set of viral vectors that express an SNCA miR designed to reduce expression of human or mouse aSyn. Ultimately, these research tools aim to address field-wide challenges in the PD preclinical tools and reagents landscape and to overall accelerate Parkinson’s disease research.
Affiliations: *The Michael J. Fox Foundation for Parkinson’s Research, **Lund University, ***Barrow Neurological Institute, ****Atuka Inc, *****GeneDetect