Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), 08035, Barcelona, Spain.
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
Nat Commun. 2024 Oct 11;15(1):8819. doi: 10.1038/s41467-024-53168-7.
One key limitation in developing effective treatments for neurodegenerative diseases is the lack of models accurately mimicking the complex physiopathology of the human disease. Humans accumulate with age the pigment neuromelanin inside neurons that synthesize catecholamines. Neurons reaching the highest neuromelanin levels preferentially degenerate in Parkinson's, Alzheimer's and apparently healthy aging individuals. However, this brain pigment is not taken into consideration in current animal models because common laboratory species, such as rodents, do not produce neuromelanin. Here we generate a tissue-specific transgenic mouse, termed tgNM, that mimics the human age-dependent brain-wide distribution of neuromelanin within catecholaminergic regions, based on the constitutive catecholamine-specific expression of human melanin-producing enzyme tyrosinase. We show that, in parallel to progressive human-like neuromelanin pigmentation, these animals display age-related neuronal dysfunction and degeneration affecting numerous brain circuits and body tissues, linked to motor and non-motor deficits, reminiscent of early neurodegenerative stages. This model could help explore new research avenues in brain aging and neurodegeneration.
开发针对神经退行性疾病的有效治疗方法的一个主要限制因素是缺乏能够准确模拟人类疾病复杂病理生理学的模型。人类随着年龄的增长，会在合成儿茶酚胺的神经元内积累色素神经黑色素。在帕金森病、阿尔茨海默病和明显健康的衰老个体中，达到最高神经黑色素水平的神经元优先退化。然而，由于常见的实验室物种（如啮齿动物）不产生神经黑色素，目前的动物模型并没有考虑到这种脑色素。在这里，我们生成了一种组织特异性的转基因小鼠，称为 tgNM，它基于人类黑色素生成酶酪氨酸酶的组成型儿茶酚胺特异性表达，模拟了人类在儿茶酚胺能区域内随年龄增长的大脑广泛分布的神经黑色素。我们发现，与渐进性的人类样神经黑色素色素沉着平行，这些动物表现出与运动和非运动缺陷相关的年龄相关的神经元功能障碍和退化，影响到许多大脑回路和身体组织，使人联想到早期神经退行性阶段。这种模型可以帮助探索大脑衰老和神经退行性变的新研究途径。
