弗里德赖希共济失调YG8R转基因小鼠的运动行为学及病理变化比较

Behavioral and pathological characterization of YG8R transgenic mouse models of Friedreich ataxia

目的比较弗里德赖希共济失调(FRDA)转基因(YG8R)小鼠运动行为学及病理变化。方法利用加速转棒实验、旷场实验、抓力实验和步态检测等行为学手段,评价YG8R转基因小鼠与同窝野生型(WT)小鼠的运动差异;免疫组化染色评价小鼠脊髓组织中神经元的死亡情况;实时荧光定量PCR(qRT-PCR)检测小鼠背根神经节(DRG)和小脑组织中Frataxin mRNA的表达水平。结果从第4个月开始,与WT组相比,YG8R小鼠的在棒时间、运动距离和抓力均明显下降(P<0.05);在第6个月,与WT组相比,YG8R小鼠的左后肢和右后肢步长距离显著下降(P<0.05),YG8R小鼠两前肢和两后肢步宽显著增加(P<0.01),右后肢的摆动时间显著下降(P<0.01),左后肢及右后肢触地时间显著增加(P<0.05);YG8R小鼠脊髓中神经元数量显著降低(P<0.01);qRT-PCR结果表明,与WT组相比,YG8R小鼠脊髓和DRG中Frataxin mRNA水平均显著降低(P<0.0001)。结论本研究进一步提供了基于GAA重复扩增的转基因YG8R小鼠FRDA模型的详细运动特征及病理变化,这将为后续研究FRDA的疾病机制和治疗提供证据。

Objective This study aimed to compare the motor behavior and pathological changes of YG8R transgenic mouse models of Friedreich ataxia(FRDA).Methods The movement behavior changes between YG8R mice and littermate wild-type(WT)mice were evaluated by the accelerated rotarod test,open field test,grip strength test and gait analysis.Real-time fluorescence-based quantitative PCR(qRT-PCR)was used to detect the Frataxin mRNA in the dorsal root ganglia(DRG)and cerebellum.Immunohistochemical staining was used to evaluate neuronal death in the mouse spinal cord tissue.Results Compared with WT mice,the time-to-fall off on an accelerating rotarod,movement distance,and grip strength of YG8R mice were significantly decreased(P<0.05)from 4 to 6 months.Compared to WT mice,YG8R mice had significantly decreased left and right hindlimb step lengths(P<0.05),increased forelimb and hindlimb step widths(P<0.01),decreased right hind limb swing time(P<0.01),and increased the touchdown time of the left and right hind limbs(P<0.05).The number of neurons in the spinal cord of YG8R mice was significantly decreased(P<0.01).The qRT-PCR results showed that frataxin mRNA levels in the spinal cord and DRG of YG8R mice were significantly decreased compared with the WT group(P<0.0001).Conclusion This study further provides detailed motor characteristics and pathological changes of the YG8R transgenic mouse models of FRDA based on GAA repeat expansion,which will be helpful for follow-up studies on the disease mechanism and treatment of FRDA.