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TitleBrain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson's disease pathogenesis.
Publication TypeJournal Article
Year of Publication2019
AuthorsCarballo-Carbajal, Iria, Ariadna Laguna, Jordi Romero-Gimenez, Thais Cuadros, Jordi Bové, Marta Martinez-Vicente, Annabelle Parent, Marta Gonzalez-Sepulveda, Núria Peñuelas, Albert Torra, Beatriz Rodríguez-Galván, Andrea Ballabio, Takafumi Hasegawa, Analía Bortolozzi, Ellen Gelpi, and Miquel Vila
JournalNat Commun
Volume10
Issue1
Pagination973
Date Published2019 03 07
ISSN2041-1723
KeywordsAging, alpha-Synuclein, Animals, Brain, Disease Models, Animal, Dopaminergic Neurons, Humans, Lewy Bodies, Male, Melanins, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Monophenol Monooxygenase, Parkinson Disease, Parkinsonian Disorders, Rats, Rats, Sprague-Dawley, Rats, Transgenic, Recombinant Proteins, Substantia Nigra
Abstract

In Parkinson's disease (PD) there is a selective degeneration of neuromelanin-containing neurons, especially substantia nigra dopaminergic neurons. In humans, neuromelanin accumulates with age, the latter being the main risk factor for PD. The contribution of neuromelanin to PD pathogenesis remains unknown because, unlike humans, common laboratory animals lack neuromelanin. Synthesis of peripheral melanins is mediated by tyrosinase, an enzyme also present at low levels in the brain. Here we report that overexpression of human tyrosinase in rat substantia nigra results in age-dependent production of human-like neuromelanin within nigral dopaminergic neurons, up to levels reached in elderly humans. In these animals, intracellular neuromelanin accumulation above a specific threshold is associated to an age-dependent PD phenotype, including hypokinesia, Lewy body-like formation and nigrostriatal neurodegeneration. Enhancing lysosomal proteostasis reduces intracellular neuromelanin and prevents neurodegeneration in tyrosinase-overexpressing animals. Our results suggest that intracellular neuromelanin levels may set the threshold for the initiation of PD.

DOI10.1038/s41467-019-08858-y
Alternate JournalNat Commun
PubMed ID30846695
PubMed Central IDPMC6405777