Kohl Zacharias, Kandasamy Mahesh, Winner Beate, Aigner Robert, Gross Claudia, Couillard-Despres Sebastien, Bogdahn Ulrich, Aigner Ludwig, Winkler Jürgen
Department of Neurology, University of Regensburg, Universitätsstr 84, Regensburg, Germany.
Brain Res. 2007 Jun 25;1155:24-33. doi: 10.1016/j.brainres.2007.04.039. Epub 2007 Apr 21.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder linked to a mutation in the huntingtin gene leading to protein aggregation in neurons. The generation of new neurons in neurogenic regions, such as the subventricular zone of the lateral ventricle and the dentate gyrus of the hippocampus, is affected by these aggregation processes. In particular, hippocampal neurogenesis is reduced in the R6/2 transgenic mouse model of HD. Since physical activity stimulates adult hippocampal neurogenesis, we examined whether running is capable to rescue the impaired hippocampal neurogenesis in R6/2 mice. Proliferation of hippocampal cells measured by proliferating cell nuclear antigen (PCNA) marker was reduced in R6/2 animals by 64% compared to wild type mice. Accordingly, newly generated neurons labeled with doublecortin (DCX) were diminished by 60% in the hippocampus of R6/2 mice. Furthermore, the number of newly generated mature neurons was decreased by 76%. Within the hippocampus of wild type animals, a four-week running period resulted in a doubling of PCNA-, DCX-, and bromo-deoxyuridine (BrdU)-labeled cells. However, physical exercise failed to stimulate proliferation and survival of newly generated neurons in R6/2 transgenic mouse model of HD. These findings suggest that mutant huntingtin alters the hippocampal microenvironment thus resulting in an impaired neurogenesis. Importantly, this adverse microenvironment impeded neurogenesis upregulation such as induced by physical exercise. Future studies need to decipher the molecular pathways involved in repressing the generation of new neurons after physical activity in huntingtin transgenic rodents.
亨廷顿舞蹈症（HD）是一种常染色体显性神经退行性疾病，与亨廷顿基因的突变有关，该突变会导致神经元中的蛋白质聚集。神经发生区域（如侧脑室的室下区和海马体的齿状回）中新神经元的生成会受到这些聚集过程的影响。特别是，在HD的R6/2转基因小鼠模型中，海马神经发生减少。由于体育活动会刺激成年海马神经发生，我们研究了跑步是否能够挽救R6/2小鼠受损的海马神经发生。与野生型小鼠相比，用增殖细胞核抗原（PCNA）标记物测量的R6/2动物海马细胞增殖减少了64%。相应地，用双皮质素（DCX）标记的新生神经元在R6/2小鼠的海马体中减少了60%。此外，新生成熟神经元的数量减少了76%。在野生型动物的海马体内，为期四周的跑步期导致PCNA、DCX和溴脱氧尿苷（BrdU）标记的细胞数量增加了一倍。然而，体育锻炼未能刺激HD的R6/2转基因小鼠模型中新生神经元的增殖和存活。这些发现表明，突变的亨廷顿蛋白改变了海马微环境，从而导致神经发生受损。重要的是，这种不利的微环境阻碍了神经发生的上调，如体育锻炼所诱导的那样。未来的研究需要破译亨廷顿转基因啮齿动物体育活动后抑制新神经元生成所涉及的分子途径。
