Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson's disease pathogenesis.
Nat Commun
; 10(1): 973, 2019 03 07.
Article
en En
| MEDLINE
| ID: mdl-30846695
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Enfermedad de Parkinson
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Encéfalo
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Monofenol Monooxigenasa
/
Melaninas
Tipo de estudio:
Etiology_studies
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Prognostic_studies
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Risk_factors_studies
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Nat Commun
Asunto de la revista:
BIOLOGIA
/
CIENCIA
Año:
2019
Tipo del documento:
Article
País de afiliación:
España