Department of Neurology, Graduate school of Medicine, Juntendo University, Tokyo, 113-8421, Japan.
Department of Neurology, Graduate school of Medicine, Juntendo University, Tokyo, 113-8421, Japan.
Neurosci Lett. 2019 Apr 23;699:59-63. doi: 10.1016/j.neulet.2019.01.042. Epub 2019 Jan 23.
Parkinson's disease (PD) is the second most common neurodegenerative disease. Lewy bodies and pale bodies in dopaminergic neurons in the substantia nigra are pathological hallmarks of PD. A number of neurodegenerative diseases demonstrate aggregate formation, but how these aggregates are associated with their pathogenesis remains unknown. It has been reported that repressor element-1 silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is induced in the nuclei of aged neurons, preserves neuronal function, and protects against neurodegeneration during aging through the repression of cell death-inducing genes. The loss of REST is associated with Alzheimer's disease pathology. However, its function in dopaminergic neurons remains unknown. Here we demonstrated that REST enters the nucleus of aged dopaminergic neurons. On the other hand, REST is partially sequestrated in Lewy bodies and is mostly absent from the nucleus of neurons in brains with PD and dementia with Lewy bodies (DLB). Dopaminergic neuron-specific autophagy-deficient mice exhibit REST accumulation in aggregates. Defects in the protein quality control system induce REST mRNA expression; its gene product mainly appears in aggregates. Our results suggest that Lewy pathology disturbs normal aging processes in dopaminergic neurons by sequestering REST and the loss of REST may associate with the PD pathology.
帕金森病（PD）是第二常见的神经退行性疾病。路易体和黑质多巴胺能神经元中的苍白体是 PD 的病理标志。许多神经退行性疾病表现出聚集物的形成，但这些聚集物如何与其发病机制相关仍不清楚。据报道，沉默元件 1 沉默转录因子/神经元抑制因子（REST/NRSF）在老年神经元的核内被诱导，通过抑制细胞死亡诱导基因来维持神经元功能并在衰老过程中防止神经变性。REST 的丧失与阿尔茨海默病的病理有关。然而，其在多巴胺能神经元中的功能仍不清楚。在这里，我们证明 REST 进入老年多巴胺能神经元的核内。另一方面，REST 部分被隔离在路易体中，并且在 PD 和路易体痴呆（DLB）患者的大脑中神经元的核内几乎不存在。多巴胺能神经元特异性自噬缺陷小鼠表现出 REST 聚集。蛋白质质量控制系统的缺陷诱导 REST mRNA 表达；其基因产物主要出现在聚集物中。我们的结果表明，路易体病理学通过隔离 REST 扰乱了多巴胺能神经元的正常衰老过程，而 REST 的丧失可能与 PD 病理学有关。
