TY - JOUR
T1 - Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis
AU - Carballo-Carbajal, Iria
AU - Laguna, Ariadna
AU - Romero-Giménez, Jordi
AU - Cuadros, Thais
AU - Bové, Jordi
AU - Martinez-Vicente, Marta
AU - Parent, Annabelle
AU - Gonzalez-Sepulveda, Marta
AU - Peñuelas, Núria
AU - Torra, Albert
AU - Rodríguez-Galván, Beatriz
AU - Ballabio, Andrea
AU - Hasegawa, Takafumi
AU - Bortolozzi, Analía
AU - Gelpi, Ellen
AU - Vila, Miquel
PY - 2019/12/1
Y1 - 2019/12/1
N2 - © 2019, The Author(s). 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.
AB - © 2019, The Author(s). 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.
U2 - 10.1038/s41467-019-08858-y
DO - 10.1038/s41467-019-08858-y
M3 - Article
C2 - 30846695
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 973
ER -