Department of Anatomy & Neurobiology, Sanger Hall, Room 9-048, 1101 E. Marshall Street, Virginia Commonwealth University Medical Campus, Box 980709, Richmond, VA 23298-0709, USA.
Brain. 2010 Mar;133(Pt 3):808-21. doi: 10.1093/brain/awp333. Epub 2010 Jan 31.
Microglia, the innate immune cells in the brain, can become chronically activated in response to dopaminergic neuron death, fuelling a self-renewing cycle of microglial activation followed by further neuron damage (reactive microgliosis), which is implicated in the progressive nature of Parkinson's disease. Here, we use an in vitro approach to separate neuron injury factors from the cellular actors of reactive microgliosis and discover molecular signals responsible for chronic and toxic microglial activation. Upon injury with the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium, N27 cells (dopaminergic neuron cell line) released soluble neuron injury factors that activated microglia and were selectively toxic to dopaminergic neurons in mixed mesencephalic neuron-glia cultures through nicotinamide adenine dinucleotide phosphate oxidase. mu-Calpain was identified as a key signal released from damaged neurons, causing selective dopaminergic neuron death through activation of microglial nicotinamide adenine dinucleotide phosphate oxidase and superoxide production. These findings suggest that dopaminergic neurons may be inherently susceptible to the pro-inflammatory effects of neuron damage, i.e. reactive microgliosis, providing much needed insight into the chronic nature of Parkinson's disease.
小胶质细胞是大脑中的固有免疫细胞，可在多巴胺能神经元死亡时被慢性激活，从而引发小胶质细胞激活的自我更新循环，随后是进一步的神经元损伤（反应性小胶质增生），这与帕金森病的进行性特征有关。在这里，我们使用体外方法将神经元损伤因子与反应性小胶质增生的细胞因子分开，并发现负责慢性和毒性小胶质细胞激活的分子信号。在使用多巴胺能神经毒素 1-甲基-4-苯基吡啶后，N27 细胞（多巴胺能神经元细胞系）释放出可溶性神经元损伤因子，这些因子激活小胶质细胞，并通过烟酰胺腺嘌呤二核苷酸磷酸氧化酶选择性地对混合中脑神经元-胶质培养物中的多巴胺能神经元有毒性。mu-钙蛋白酶被鉴定为受损神经元释放的关键信号，通过激活小胶质细胞烟酰胺腺嘌呤二核苷酸磷酸氧化酶和超氧化物的产生，导致选择性的多巴胺能神经元死亡。这些发现表明，多巴胺能神经元可能容易受到神经元损伤的促炎作用（即反应性小胶质增生）的影响，这为帕金森病的慢性特征提供了急需的深入了解。
