Department of Neuroscience of Disease, Center for Transdisciplinary Research, Niigata University, Niigata 951-8585, Japan; Brain Research Institute, Niigata University, Niigata 951-8585, Japan; Department of Neuroscience, University of Miyazaki, Faculty of Medicine, Miyazaki 889-1692, Japan.
Frontier Science Research Center, University of Miyazaki, Miyazaki 889-1692, Japan.
Cell Rep. 2019 Feb 12;26(7):1727-1733.e6. doi: 10.1016/j.celrep.2019.01.015.
Parkinson's disease (PD) is a neurodegenerative disease characterized by α-synuclein-positive inclusion bodies and loss of neurons, including dopaminergic neurons. Difficulty in replicating PD phenotypes using animal models partly limits the understanding of PD and the therapy required. Although PD is strongly associated with aging, most experimental animals may not exhibit age-related symptoms. Herein, we demonstrate that Nothobranchius furzeri, a rapidly aging teleost with a short life span, exhibits age-dependent degeneration of dopaminergic and noradrenergic neurons and progression of α-synuclein pathologies. These pathological phenotypes are similar to those observed in human patients with PD. Amelioration of the cell loss by genetic depletion of α-synuclein suggests that α-synuclein is not a bystander but a causative protein of neurodegeneration. N. furzeri can reveal mechanisms underlying PD, especially of the idiopathic form that affects a majority of patients with PD, including α-synuclein-dependent neurodegeneration, age-dependent phenotypes, and progression of α-synuclein pathology.
帕金森病（PD）是一种神经退行性疾病，其特征是存在α-突触核蛋白阳性包涵体和神经元丧失，包括多巴胺能神经元。使用动物模型复制 PD 表型存在困难，这在一定程度上限制了对 PD 的理解和所需的治疗。尽管 PD 与衰老密切相关，但大多数实验动物可能不会表现出与年龄相关的症状。在此，我们证明，短寿命的快速衰老硬骨鱼非洲鲫鱼（Nothobranchius furzeri）表现出多巴胺能和去甲肾上腺素能神经元的年龄依赖性退化以及α-突触核蛋白病理的进展。这些病理表型与人类 PD 患者观察到的表型相似。通过基因敲除α-突触核蛋白减轻细胞丢失表明，α-突触核蛋白不是旁观者，而是神经退行性变的致病蛋白。N. furzeri 可以揭示 PD 的机制，特别是影响大多数 PD 患者的特发性形式的机制，包括α-突触核蛋白依赖性神经退行性变、年龄依赖性表型和α-突触核蛋白病理的进展。
