Zebrafish: a New Model of Parkinson’s Disease

Todas as afirmações efectuadas no presente documento são de exclusiva responsabilidade do seu autor, não cabendo qualquer responsabilidade à Faculdade de Medicina da Universidade de Lisboa pelos conteúdos nele apresentados. Abstract Parkinson´s disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, affecting around 2% of the population with more than 65 years. The first gene implicated with PD was SNCA that encodes to alpha-synuclein. At the neuronal level, this protein was found in the Lewy Bodies, one of the pathologic hallmarks of the disease and it has been identified both in sporadic and familiar cases of PD. Its role in the disease is still unclear. Besides alpha-synuclein, other 15 genetic loci have been associated to PD. To clarify the role of alpha-synuclein in PD, several in vivo models have been developed, expressing wild-type and PD-associated mutant forms of the protein. However, none of the existing models fully recapitulates all of the hallmarks of the disease. To circumvent this limitation, new models must be developed. Zebrafish has been widely used as an animal model for studying several human disorders because, besides being a vertebrate, it has all the molecular background and bioimaging characteristics suitable for these studies. Here, we started to generate a Zebrafish transgenic model for human alpha-synuclein. In addition, through bioinformatic analysis, we found that four PD related genes encoding ATP13a2, Lrrk2, Synphilin-1, and Glucocerebrosidase, display high homology rates when compared to the human gene sequences. Moreover, despite a high homology in the entire sequence, specific conserved domains sequences are also highly homologous, suggesting a conserved functionality of the genes. In situ hybridization of ATP13a2 revealed that, although initially expressed in whole embryo's body, it becomes more restricted to the brain area along the embryonic development. The generation of this novel PD transgenic model will allow further studies to better understand the mechanisms underlying the disease pathology. Taken together, these results will provide a novel and powerful system to explore more the molecular basis of PD and to open novel avenues for therapeutic intervention. Zebrafish: a new model of Parkinson's disease |Abstract ii Resumo A doença de Parkinson (PD) é a segunda doença neurodegenerativa mais comum os respectivos genes humanos. Esta homologia estende-se aos domínios funcionais que são idênticos entre as sequências indicando uma funcionalidade conservada dos genes. Através da técnica que hibridização in situ, demonstrámos que o gene ATP13a2 tem uma expressão ubíqua ao longo …