Neuromelanin accumulation drives endogenous synucleinopathy in non-human primates
Although neuromelanin is a dark pigment characteristic of dopaminergic neurons in the human substantia nigra pars compacta, its potential role in the pathogenesis of Parkinson's disease (PD) has often been neglected since most commonly used laboratory animals lack neuromelanin. Here we took adv...
| Autores: | , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Servizo Galego de Saúde (SERGAS) |
| Repositorio: | RUNA. Repositorio da Consellería de Sanidade e Sergas |
| OAI Identifier: | oai:runa.sergas.gal:20.500.11940/21779 |
| Acceso en línea: | https://portalcientifico.sergas.gal//documentos/657f1a7b3ea324404509b443 http://hdl.handle.net/20.500.11940/21779 |
| Access Level: | acceso abierto |
| Palabra clave: | Animals Humans Aged Synucleinopathies Substantia Nigra alpha-Synuclein Parkinson Disease Primates AS A Coruña AS Coruña AP AS Santiago IDIS |
| Sumario: | Although neuromelanin is a dark pigment characteristic of dopaminergic neurons in the human substantia nigra pars compacta, its potential role in the pathogenesis of Parkinson's disease (PD) has often been neglected since most commonly used laboratory animals lack neuromelanin. Here we took advantage of adeno-associated viral vectors encoding the human tyrosinase gene for triggering a time-dependent neuromelanin accumulation within substantia nigra pars compacta dopaminergic neurons in macaques up to similar levels of pigmentation as observed in elderly humans. Furthermore, neuromelanin accumulation induced an endogenous synucleinopathy mimicking intracellular inclusions typically observed in PD together with a progressive degeneration of neuromelanin-expressing dopaminergic neurons. Moreover, Lewy body-like intracellular inclusions were observed in cortical areas of the frontal lobe receiving dopaminergic innervation, supporting a circuit-specific anterograde spread of endogenous synucleinopathy by permissive trans-synaptic templating. In summary, the conducted strategy resulted in the development and characterization of a new macaque model of PD matching the known neuropathology of this disorder with unprecedented accuracy. Most importantly, evidence is provided showing that intracellular aggregation of endogenous ?-synuclein is triggered by neuromelanin accumulation, therefore any therapeutic approach intended to decrease neuromelanin levels may provide appealing choices for the successful implementation of novel PD therapeutics. |
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