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Nat Commun. 2019 Mar 7;10(1):973. doi: 10.1038/s41467-019-08858-y.

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

Author information

1
Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), 08035, Barcelona, Spain.
2
Telethon Institute of Genetics and Medicine (TIGEM), 80078, Naples, Italy.
3
Department of Neurology, Tohoku University School of Medicine, Miyagi, 980-8574, Japan.
4
Department of Neurochemistry and Neuropharmacology, IIBB-CSIC, August Pi i Sunyer Biomedical Research Institute (IDIBAPS)-Center for Networked Biomedical Research on Mental Health (CIBERSAM), 08036, Barcelona, Spain.
5
Neurological Tissue Bank, Biobanc Hospital Clínic-IDIBAPS, 08036, Barcelona, Spain.
6
Institute of Neurology, Medical University of Vienna, 1090, Vienna, Austria.
7
Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), 08035, Barcelona, Spain. miquel.vila@vhir.org.
8
Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, 08193, Barcelona, Spain. miquel.vila@vhir.org.
9
Catalan Institution for Research and Advanced Studies (ICREA), 08010, Barcelona, Spain. miquel.vila@vhir.org.

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.

PMID:
30846695
PMCID:
PMC6405777
DOI:
10.1038/s41467-019-08858-y
[Indexed for MEDLINE]
Free PMC Article

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