Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis

Iria Carballo-Carbajal, Ariadna Laguna, Jordi Romero-Giménez, 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 ()
Additional contact information
Iria Carballo-Carbajal: Vall d’Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED)
Ariadna Laguna: Vall d’Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED)
Jordi Romero-Giménez: Vall d’Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED)
Thais Cuadros: Vall d’Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED)
Jordi Bové: Vall d’Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED)
Marta Martinez-Vicente: Vall d’Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED)
Annabelle Parent: Vall d’Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED)
Marta Gonzalez-Sepulveda: Vall d’Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED)
Núria Peñuelas: Vall d’Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED)
Albert Torra: Vall d’Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED)
Beatriz Rodríguez-Galván: Vall d’Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED)
Andrea Ballabio: Telethon Institute of Genetics and Medicine (TIGEM)
Takafumi Hasegawa: Tohoku University School of Medicine
Analía Bortolozzi: August Pi i Sunyer Biomedical Research Institute (IDIBAPS)-Center for Networked Biomedical Research on Mental Health (CIBERSAM)
Ellen Gelpi: Biobanc Hospital Clínic-IDIBAPS
Miquel Vila: Vall d’Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED)

Nature Communications, 2019, vol. 10, issue 1, 1-19

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08858-y

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