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]

參考譯文

中腦黑質(zhì)多巴胺能神經(jīng)元的丟失導(dǎo)致帕金森病的發(fā)生，目前為止帕金森病只能采取對(duì)癥治療，尚無(wú)有效阻止或治愈多巴胺能神經(jīng)元退行性變發(fā)生的有效治療方法。阻礙神經(jīng)保護(hù)治療的瓶頸在于導(dǎo)致神經(jīng)退行性變的分子機(jī)制尚不清楚。帕金森致病基因的發(fā)現(xiàn)提示蛋白質(zhì)錯(cuò)誤折疊以及泛素-蛋白酶體功能異?？赡苁桥两鹕〉闹饕l(fā)病機(jī)制。而先前認(rèn)為帕金森病發(fā)病中神經(jīng)退行性改變、線粒體功能異常以及氧化應(yīng)激等因素的發(fā)病原因,在對(duì)多巴胺能神經(jīng)元產(chǎn)生直接的毒性損傷的同時(shí)還在錯(cuò)誤折疊蛋白的異常聚集中發(fā)揮部分作用。神經(jīng)毒素誘導(dǎo)的帕金森病模型尤其是MPTP模型為探索多巴胺能神經(jīng)元死亡中的多級(jí)分子通路提供了巨大幫助,同時(shí)通過(guò)基因操縱產(chǎn)生的帕金森病模型為探求黑質(zhì)多巴胺能神經(jīng)元對(duì)退行性變選擇易感性等方面發(fā)揮著重要作用。

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