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Title:          In vivo reduction of age-dependent neuromelanin accumulation mitigates features of Parkinson’s disease
Subject:        DOI: 10.1093/brain/awac445; Brain, 146, 3, 2023-01-30.; Abstract: 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, 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 build-up 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 substantia nigra 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 ageing.
Keywords:       Parkinson’s disease; neuromelanin; VMAT2; dopamine; substantia nigra
Author:         Marta Gonzalez-Sepulveda
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      Title: In vivo reduction of age-dependentneuromelanin accumulation mitigatesfeatures of Parkinson’s disease
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        Title: Introduction
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        Title: Materials and methods
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          Title: VMAT2 overexpression reduces catechol oxidation, NM production and LB-like inclusion formation in humanized rats
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          Title: VMAT2 overexpression prevents NM-linked neurodegeneration
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          Title: Attenuated neurodegeneration by VMAT2 overexpression is associated to decreased extracellular NM debris and inflammation
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          Title: Preservation of striatal DA levels and metabolism by VMAT2 overexpression prevents motor deficits in NM-producing rats
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   Type: CRC32
  Checksum: b99d45cad9d37392521cc86c6bd2f666
   Type: MD5
  Checksum: 03bb22ac6d24b7ed0032e9731341ad01d61fb591
   Type: SHA-1