In vivo reduction of age-dependent neuromelanin accumulation mitigates features of Parkinson's disease
González Sepúlveda, Marta (Hospital Universitari Vall d'Hebron)
Compte, Joan (Vall d'Hebron Institut de Recerca (VHIR))
Cuadros, Thais (Vall d'Hebron Institut de Recerca (VHIR))
Nicolau Vera, Alba (Vall d'Hebron Institut de Recerca (VHIR))
Guillard-Sirieix, Camille (Vall d'Hebron Institut de Recerca (VHIR))
Peñuelas, Núria (Vall d'Hebron Institut de Recerca (VHIR))
Lorente-Picon, Marina (Vall d'Hebron Institut de Recerca (VHIR))
Parent, Annabelle (Vall d'Hebron Institut de Recerca (VHIR))
Romero-Giménez, Jordi (Vall d'Hebron Institut de Recerca (VHIR))
Cladera-Sastre, Joana M. (Vall d'Hebron Institut de Recerca (VHIR))
Laguna, Ariadna (Vall d'Hebron Institut de Recerca (VHIR))
Vila Bover, Miquel
Universitat Autònoma de Barcelona

Fecha:	2023
Resumen:	Humans accumulate with age the dark-brown pigment neuromelanin inside specific neuronal groups. Neurons with the highest neuromelanin levels are particularly susceptible to degeneration in Parkinson's disease, especially dopaminergic neurons of the substantia nigra, the loss of which leads to characteristic motor Parkinson's disease symptoms. In contrast to humans, neuromelanin does not appear spontaneously in most animals, including rodents, and Parkinson's disease is an exclusively human condition. Using humanized neuromelanin-producing rodents, we recently found that neuromelanin can trigger Parkinson's disease pathology when accumulated above a specific pathogenic threshold. Here, by taking advantage of this newly developed animal model, we assessed whether the intracellular build-up of neuromelanin that occurs with age can be slowed down in vivo to prevent or attenuate Parkinson's disease. Because neuromelanin derives from the oxidation of free cytosolic dopamine, we enhanced dopamine vesicular encapsulation in the substantia nigra of neuromelanin-producing rats by viral vector-mediated overexpression of vesicular monoamine transporter 2 (VMAT2). This strategy reduced the formation of potentially toxic oxidized dopamine species that can convert into neuromelanin and maintained intracellular neuromelanin levels below their pathogenic threshold. Decreased neuromelanin production was associated with an attenuation of Lewy body-like inclusion formation and a long-term preservation of dopamine homeostasis, nigrostriatal neuronal integrity and motor function in these animals. Our results demonstrate the feasibility and therapeutic potential of modulating age-dependent intracellular neuromelanin production in vivo, thereby opening an unexplored path for the treatment of Parkinson's disease and, in a broader sense, brain ageing. Neurons that accumulate the highest levels of neuromelanin with age are also the most susceptible to degeneration in Parkinson's disease. Using a neuromelanin-producing rat model, Gonzalez-Sepulveda, Compte et al. show that slowing down age-dependent neuromelanin production can help prevent Parkinson's disease-like features.
Ayudas:	"la Caixa" Foundation LCF/BQ/DI18/1166063 "la Caixa" Foundation LCF/BQ/PR19/11700005 Agencia Estatal de Investigación PID2020-116339RB-I00 Instituto de Salud Carlos III AC20/00121
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Parkinson's disease ; Neuromelanin ; VMAT2 ; Dopamine ; Substantia nigra
Publicado en:	Brain, Vol. 146 (january 2023) , p. 1040-1052, ISSN 1460-2156

DOI: 10.1093/brain/awac445
PMID: 36717986

13 p, 861.5 KB

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