Abstract: The development of clinical candidates that modify the natural progression of sporadic Parkinson’s disease and related synucleinopathies is a praiseworthy endeavor, but extremely challenging. Therapeutic candidates that were successful in preclinical Parkinson’s disease animal models have repeatedly failed when tested in clinical trials. While these failures have many possible explanations, it is perhaps time to recognize that the problem lies with the animal models rather than the putative candidate. In other words, the lack of adequate animal models of Parkinson’s disease currently represents the main barrier to preclinical identification of potential disease-modifying therapies likely to succeed in clinical trials. However, this barrier may be overcome by the recent introduction of novel generations of viral vectors coding for different forms of alpha-synuclein species and related genes. Although still facing several limitations, these models have managed to mimic the known neuropathological hallmarks of Parkinson’s disease with unprecedented accuracy, delineating a more optimistic scenario for the near future.

Key words: adeno-associated viral vectors, alpha-synuclein, dopamine, Lewy bodies, neurodegeneration, neuromelanin, neuropathology, substantia nigra