Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute (VHIR)-Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), 08035 Barcelona, Spain.
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.
Brain. 2023 Mar 1;146(3):1040-1052. doi: 10.1093/brain/awac445.
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.
随着年龄的增长，人类会在特定神经元群体中积累深褐色的色素神经黑色素。神经黑色素含量最高的神经元特别容易在帕金森病中退化，尤其是黑质中的多巴胺能神经元，这些神经元的丧失导致了典型的运动性帕金森病症状。与人类不同的是，神经黑色素在大多数动物中，包括啮齿类动物，不会自发出现，而帕金森病是一种人类特有的疾病。使用具有人类化神经黑色素产生能力的啮齿动物，我们最近发现，当神经黑色素积累超过特定的致病阈值时，它可以引发帕金森病病理。在这里，我们利用这种新开发的动物模型，评估了体内神经黑色素随年龄的积累是否可以减缓，以预防或减轻帕金森病。由于神经黑色素源自游离胞质多巴胺的氧化，我们通过病毒载体介导的囊泡单胺转运体 2（VMAT2）过表达，增强了神经黑色素产生大鼠黑质中的多巴胺囊泡封装。这种策略减少了潜在毒性的氧化多巴胺的形成，这些多巴胺可以转化为神经黑色素，并将细胞内神经黑色素水平维持在致病阈值以下。神经黑色素生成的减少与 Lewy 体样包涵体形成的减弱以及这些动物中多巴胺稳态、黑质纹状体神经元完整性和运动功能的长期维持有关。我们的结果表明，在体内调节与年龄相关的细胞内神经黑色素生成是可行的，并且具有治疗潜力，从而为帕金森病的治疗开辟了一条未探索的途径，更广泛地说，为大脑衰老开辟了一条途径。
