Zuccato Chiara, Liber Daniel, Ramos Catarina, Tarditi Alessia, Rigamonti Dorotea, Tartari Marzia, Valenza Marta, Cattaneo Elena
Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milano, Via Balzaretti 9, 20133 Milano, Italy.
Pharmacol Res. 2005 Aug;52(2):133-9. doi: 10.1016/j.phrs.2005.01.001.
Huntingtin is a protein of 348 kDa that is mutated in Huntington's disease (HD), a dominantly inherited neurodegenerative disorder. Previous data have led us to propose that aspects of the disease arise from both a loss of the neuroprotective function of the wild-type protein, and a toxic activity gained by the mutant protein. In particular, we have shown that wild-type huntingtin stimulates the production of brain-derived neurotrophic factor (BDNF), a pro-survival factor for the striatal neurons that die in the pathology. Wild-type huntingtin controls BDNF gene transcription in cerebral cortex, which is then delivered to its striatal targets. In the disease state, supply of cortical BDNF to the striatum is strongly reduced, possibly leading to striatal vulnerability. Here we show that a reduction in cortical BDNF messenger level correlates with the progression of the disease in a mouse model of HD. In particular, we show that the progressive loss of mRNAs transcribed from BDNF exon II, III and IV follows a different pattern that may reflect different upstream mechanisms impaired by mutation in huntingtin. On this basis, we also discuss the possibility that delivery of BDNF may represent an useful strategy for Huntington's disease treatment.
亨廷顿蛋白是一种分子量为348 kDa的蛋白质，在亨廷顿舞蹈病（HD）中发生突变，HD是一种常染色体显性遗传的神经退行性疾病。先前的数据使我们提出，该疾病的某些方面源于野生型蛋白神经保护功能的丧失以及突变蛋白获得的毒性活性。特别是，我们已经表明，野生型亨廷顿蛋白可刺激脑源性神经营养因子（BDNF）的产生，BDNF是在该病理过程中死亡的纹状体神经元的一种促存活因子。野生型亨廷顿蛋白控制大脑皮质中BDNF基因的转录，然后将其输送到纹状体靶点。在疾病状态下，纹状体中皮质BDNF的供应大幅减少，这可能导致纹状体易损性。在此我们表明，在HD小鼠模型中，大脑皮质BDNF信使水平的降低与疾病进展相关。特别是，我们表明，从BDNF外显子II、III和IV转录的mRNA的逐渐丧失遵循不同的模式，这可能反映了亨廷顿蛋白突变损害的不同上游机制。在此基础上，我们还讨论了BDNF递送可能代表亨廷顿舞蹈病治疗有用策略的可能性。
