Gene Therapy to Modulate Alpha-Synuclein in Synucleinopathies

The protein alpha-Synuclein (alpha-Syn) is a key contributor to the etiology of Parkinson's disease (PD) with aggregation, trans-neuronal spread, and/or depletion of alpha-Syn being viewed as crucial events in the molecular processes that result in neurodegeneration. The exact succession of pathological occurrences that lead to neuronal death are still largely unknown and are likely to be multifactorial in nature. Despite this unknown, alpha-Syn dose and stability, autophagy-lysosomal dysfunction, and inflammation, amongst other cellular impairments, have all been described as participatory events in the neurodegenerative process. To that end, in this review we discuss the logical points for gene therapy to intervene in alpha-Syn-mediated disease and review the preclinical body of work where gene therapy has been used, or could conceptually be used, to ameliorate alpha-Syn induced neurotoxicity. We discuss gene therapy in the traditional sense of modulating gene expression, as well as the use of viral vectors and nanoparticles as methods to deliver other therapeutic modalities.