Parkinson's disease (PD) results primarily from the death of dopaminergic neurons in the substantia nigra. Current PD medications treat symptoms; none halt or retard dopaminergic neuron degeneration. The main obstacle to developing neuroprotective therapies is a limited understanding of the key molecular events that provoke neurodegeneration. The discovery of PD genes has led to the hypothesis that misfolding of proteins and dysfunction of the ubiquitin-proteasome pathway are pivotal to PD pathogenesis. Previously implicated culprits in PD neurodegeneration, mitochondrial dysfunction and oxidative stress, may also act in part by causing the accumulation of misfolded proteins, in addition to producing other deleterious events in dopaminergic neurons. Neurotoxin-based models (particularly MPTP) have been important in elucidating the molecular cascade of cell death in dopaminergic neurons. PD models based on the manipulation of PD genes should prove valuable in elucidating important aspects of the disease, such as selective vulnerability of substantia nigra dopaminergic neurons to the degenerative process.

                                                                   [Neuron,2006;52(1):33-38]

参考译文

中脑黑质多巴胺能神经元的丢失导致帕金森病的发生，目前为止帕金森病只能采取对症治疗，尚无有效阻止或治愈多巴胺能神经元退行性变发生的有效治疗方法。阻碍神经保护治疗的瓶颈在于导致神经退行性变的分子机制尚不清楚。帕金森致病基因的发现提示蛋白质错误折叠以及泛素-蛋白酶体功能异常可能是帕金森病的主要发病机制。而先前认为帕金森病发病中神经退行性改变、线粒体功能异常以及氧化应激等因素的发病原因,在对多巴胺能神经元产生直接的毒性损伤的同时还在错误折叠蛋白的异常聚集中发挥部分作用。神经毒素诱导的帕金森病模型尤其是MPTP模型为探索多巴胺能神经元死亡中的多级分子通路提供了巨大帮助,同时通过基因操纵产生的帕金森病模型为探求黑质多巴胺能神经元对退行性变选择易感性等方面发挥着重要作用。

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