PT - JOURNAL ARTICLE AU - Gonzalez-Sepulveda, Marta AU - Compte, Joan AU - Cuadros, Thais AU - Nicolau, Alba AU - Guillard-Sirieix, Camille AU - Peñuelas, Núria AU - Lorente-Picon, Marina AU - Parent, Annabelle AU - Romero-Giménez, Jordi AU - Cladera-Sastre, Joana M. AU - Laguna, Ariadna AU - Vila, Miquel TI - In vivo reduction of age-dependent neuromelanin accumulation mitigates features of Parkinson’s disease AID - 10.1101/2022.08.08.503142 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.08.08.503142 4099 - http://biorxiv.org/content/early/2022/08/11/2022.08.08.503142.short 4100 - http://biorxiv.org/content/early/2022/08/11/2022.08.08.503142.full AB - Humans accumulate with age the dark-brown pigment neuromelanin inside specific neuronal groups. Neurons with the highest neuromelanin levels are particularly susceptible to degeneration in Parkinson’s disease, especially dopaminergic neurons of the substantia nigra (SN), the loss of which leads to characteristic motor Parkinson’s disease symptoms. In contrast to humans, neuromelanin does not appear spontaneously in most animals, including rodents, and Parkinson’s disease is an exclusively human condition. Using humanized neuromelanin-producing rodents, we recently found that neuromelanin can trigger Parkinson’s disease pathology when accumulated above a specific pathogenic threshold.Here, by taking advantage of this newly developed animal model, we assessed whether the intracellular buildup of neuromelanin that occurs with age can be slowed down in vivo to prevent or attenuate Parkinson’s disease. Because neuromelanin derives from the oxidation of free cytosolic dopamine, we enhanced dopamine vesicular encapsulation in the SN of neuromelanin-producing rats by viral vector-mediated overexpression of vesicular monoamine transporter 2 (VMAT2). This strategy reduced the formation of potentially toxic oxidized dopamine species that can convert into neuromelanin and maintained intracellular neuromelanin levels below their pathogenic threshold. Decreased neuromelanin production was associated with an attenuation of Lewy body-like inclusion formation and a long-term preservation of dopamine homeostasis, nigrostriatal neuronal integrity and motor function in these animals.Our results demonstrate the feasibility and therapeutic potential of modulating age-dependent intracellular neuromelanin production in vivo, thereby opening an unexplored path for the treatment of Parkinson’s disease and, in a broader sense, brain aging.Competing Interest StatementThe authors have declared no competing interest.