Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson\u2019s disease pathogenesis

Iria Carballo-Carbajal,Marta Martinez-Vicente,Marta Gonzalez-Sepulveda,Núria Peñuelas,Jordi Bové,Takafumi Hasegawa,Beatriz Rodríguez-Galván,Analía Bortolozzi,Ariadna Laguna,Thais Cuadros,Ellen Gelpi,Miquel Vila,Jordi Romero-Giménez,Annabelle Parent,Albert Torra,Andrea Ballabio

doi:10.1038/s41467-019-08858-y

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.

Highlights

In Parkinson’s disease (PD) there is a selective degeneration of neuromelanin-containing neurons, especially substantia nigra dopaminergic neurons
It is well-established that the synthesis of peripheral melanins, which occurs within specialized cells, results from an enzymatically driven biosynthetic pathway initiated with the hydroxylation of L-tyrosine to L-DOPA, followed by the oxidation of L-DOPA to the melanin precursor DOPAquinone, in which tyrosinase is the key, rate-limiting enzyme[18,19]
In the present work, we have generated the first experimental in vivo model of age-dependent production and intracellular accumulation of human-like NM within PD-vulnerable substantia nigra pars compacta (SNpc) DA neurons, up to levels reached in elderly humans

Summary

Introduction

In Parkinson’s disease (PD) there is a selective degeneration of neuromelanin-containing neurons, especially substantia nigra dopaminergic neurons. Classical Lewy bodies (LB), i.e. aSyncontaining intracytoplasmic inclusion bodies that represent the pathological hallmark of the disease, as well as their presumed precursor structures, pale bodies (PB), typically appear within the intracellular areas of the cytoplasm in which NM accumulates and form in close physical association with this pigment[11] Along this line, studies in human brains have shown that aSyn redistributes to the lipid component of NM at early PD stages[12] and that aSyn becomes entrapped within NM granules extracted from PD, but not control, brains[13]. A factor so intimately linked to PD such as NM has been surprisingly neglected so far in experimental in vivo paradigms of the disease To address this major limitation, in the present study we generate the first rodent model of agedependent human-like NM production in SNpc DA neurons at levels up to those reached in elderly humans. We show that progressive intracellular NM accumulation above a specific threshold is associated with a PD phenotype

Methods

Results

Conclusion