帕金森病(Parkinson's disease,PD)是一种中老年常见的进行性神经系统变性疾病,其病理特征为黑质致密部多巴胺能神经元选择性、进行性的丧失和残存神经元内出现Lewy小体.目前认为约10%的患者为遗传性的,约90%的患者为散发性的.到目前为止,散发性PD的病因及发病机制尚不完全清楚.最近的多个研究提示蛋白酶体功能下降导致神经元内异常蛋白聚集,功能紊乱,并进一步造成神经元的凋亡,可能参与了散发性PD的发病.本文就蛋白酶体功能下降与散发性PD发病机制方面的研究进展做一综述。

Objective To observe nigral degeneration with inclusion body formation in rats and their behavioral changes after treatment with proteasome inhibitor, and investigate the role ofproteasomal dysfunction in the pathogenesis of Parkinson disease. Methods Lactacystin, a selective proteasome inhibitor, was injected stereotaxically into the lett substantia nigral pars compacta of the rats, and an equal volume of saline was injected in the control group. Spontaneous behavioral abnormalities and apomorphine-induced contralateral rotations of the rats were observed after the injection. The pathological changes in the substantia nigra were detected using Nissl staining, and the expressions of tyrosine hydroxylase (TH) and a-synuclein in the substantia nigra and TH expression in the striatum were investigated by immunohistochemistry. The ultrastructural changes in the substantia nigral pars compacta were observed with transmission electron microscope. Results Seven days after lactacystin injection, the rats exhibited reduced apontaneous activities, tremor, progressive bradykinesia, and apomorphine-induced contralateral rotation. Nissl staining 3 weeks after lactacystin injection revealed significantly reduced neurons in the lett substantia nigra pars compacta and loosened structures of the Nissl bodies;immunohistochemistry demonstrated obvious degeneration in the lett substantia nigra pars compacta, where the TH-positive cells were significantly decreased with enhanced expression of a-synuclein. The number of TH-positive fibers in the striamm was significantly reduced 3 weeks afterlactacystin injection, and electron microscopy revealed the formation of inclusion bodies as a result of protein aggregation. Conclusion Lactacystin injected stereotaxically into the lett substantia nigrai pars compacta can induce substantia nigra degeneration, inclusion body formation and behavioral changes in rats, suggesting the applicability of lactacystin for establishment of animal models of Parkinson disease. Proteasomal dysfunction may play an important role in the pathogenesis of Parkinson disease.

Objective To investigate the role of proteasomal dysfunction in the pathogenesis of Parkinson disease and whether the changes of inducible nitric oxide synthase in the substantia nigra of model rats are involved in the degeneration of dopaminergic (DA) neurons induced by proteasome inhibitor lactacystin. Methods Thirty healthy SD male rats are equally divided into 5 groups (saline control and 1-day, 3-day, 1-week and 3-week groups). Lactacystin was stereotaxically infused unilaterally into the substantia nigra of the rats, and the behavioral alterations of rats at different time points were recorded. The degeneration of DA neurons and the changes of inducible nitric oxide synthase in the substantia nigra of all the groups were detected by immunohistochemistry. Results The rats presented with reduction of spontaneous activity and apomorphine-induced contralateral rotation on the 7th day after lactacystin injection. On the 21th day after the injection of lactacystin, the number of apomorphine-induced contralateral rotations in 30 minutes was 258.90±11.56. The number of TH-positive cells in the central nervous system was decreased significantly in the 3-week group. The numbers of iNOS positive cells in the central nervous system was increased dramatically after 1 day with lactacystin injection and peaked on the 3rd day, started to decrease on the 7th day and virtually disappeared at the 21th day. Conclusion The dysfunction of proteasome may play a trigger role in the pathogenesis of Parkinson disease. Up-regulation of iNOS may be one of the crucial mechanisms in Lactacystin-induced degeneration of DA neurons.

Objective To observe the nigral degeneration and motor behavior changes induced by proteasome inhibitor in the substantia nigra, and to investigate the role of proteasomal dysfunction in the pathogenesis of Parkinson's disease. Methods Lactacystin, a selective proteasome inhibitor, was unilaterally injected stereotaxically into the left substantia nigral pars compacta of rats. Equal volume of saline were injected in control group. The spontaneous behavioral abnormalities, apomorphine-induced contralateral rotations of rats and the spontaneous motor behavioral changes in the open-field were observed. The expressions of tyrosine hydroxylase in substantia nigra and striatum was investigated by immunohistochemistry. Results The rats became progressively bradykinetic and displayed contralateral head tilting, tremor and apomorphine-induced contralateral rotation 7 days after Lactacystin injection. The spontaneous motor behavior of rats in Lactacystin group changed in open-field test. The numbers of TH-positive cells in left SNc and TH-positive nerve fibers in left striatum in Lactacystin group significantly decreased. Conclusion Lactacystin, a selective proteasome inhibitor, unilaterally injected stereotaxically into the left substantia nigral pars compacta of rats, can induce the degeneration of substantia nigra and motor behavioral changes of rats. Lactacystin may be used for the establishment of new PD animal model. Proteasomal dysfunction may play an important role in the pathogenesis of PD.

中央中核-束旁核复合体(center median-parafascicular complex,CM-Pf)是丘脑板内核群的重要组成部分,它与丘脑内其他核团、基底核及大脑皮层有着丰富的纤维联系[1-3],可是既往较少受到研究者们的注意.但是随着深部脑刺激术作为运动障碍性疾病[4]和顽固性疼痛[3]等功能性神经疾病的治疗方法被人们接受,CM-Pf复合体作为有效靶点[3],而重新受到研究者们的关注,在基础、临床应用等多方面被广泛研究。

Objective To investigate Skp2 protein expression in gliomas and its correlation with malignancy of gliomas and prognosis in the patients. Methods Paraffin-embedded samples of gliomas were collected from 52 patients, including 25 grade Ⅰ-Ⅱ and 27 grade Ⅲ-Ⅳ gliomas. The expression levels of Skp2 protein and Ki-67 nuclear antigen were determined by immunohistochemical methods. Meanwhile, the patients were followed up during their overall survival period. Results The positive percentages of Skp2 expression in grade Ⅰ-Ⅱand grade Ⅲ-Ⅳ were 56% and 81.5%, respectively. The statistical difference between two groups was significant (P0.01). There was a positive correlation between Skp2 and Ki-67 expressions (r = 0.818, P0.01). The Ki-67 labeling index of glioma cells with positive Skp2 expression was higher than that with negative Skp2 expression (P0.05). According to the Kaplan-Meier curves, the high Skp2 expression group (Skp2 LI15%) showed significantly shorter overall survival time than that of low Skp2 expression group (P0.05). Conclusion Overexpression of Skp2 may play a role in the malignancy of gliomas. Detecting the expression level of Skp2 protein will be helpful to evaluate the biological behaviors of gliomas and prognosis in the patients.