Machado-Joseph病动物模型研究进展

Research Progress on Mouse Models of Machado-Joseph Disease

Machado-Joseph病（MJD）又称脊髓小脑共济失调3型（SCA3）,是常染色体显性遗传小脑共济失调（ADCAs）的一种,属于一类遗传性神经退行性疾病。其致病基因为MJD1（也称ATXN3）。到目前为止在颅内表达全长突变ataxin-3蛋白的MJD转基因小鼠模型已建立,本文主要对这些动物模型进行了比较。它们的主要区别在于DNA结构的不同,表现在ataxin-3亚型、多聚谷氨酰胺（polyQ）数量及转基因表达启动子的不同。大多数动物模型从体重、平衡、步态、肢体姿势、活动及死亡年龄等行为学改变进行了表型分析。病理分析主要包括小脑深部核团、脑桥、丘脑底核、黑质、脊髓小脑核团神经元及Purkinje细胞是否发生神经退行性变,并量化分析核内包涵体及神经元数量。实验室应重视利用目前已有的MJD/SCA3动物模型或制作新的动物模型从推迟疾病发生、延缓疾病进展、清除神经元核内包涵体、延长寿命等方面找到治疗新靶点。

Machado-Joseph disease（MJD）,also called spinocerebellar ataxia type 3（SCA3）,is one of autosomal dominant cerebellar ataxias（ADCAs）that are hereditary neurodegenerative disorders.The pathogenic gene is MJD1（also known as ATXN3）.The MJD transgenic mouse model,which expresses the full-length mutant ataxin-3 protein in the brain,has been established,and the animal models are compared in this review.The main difference among them was in transgenic DNA constructs that include the encoded ataxin-3 isoform（s）,number of polyglutamine（s）（polyQ）and promoters driving transgene expression.Most models were evaluated in behaviors such as body weight,balance/coordination,gait,limb position,locomotor activity,and age of death.The pathological analysis includes the presence of neuronal intranuclear inclusions in the deep cerebellar nucleus,pons,subthalamic nucleus,substantia nigra,cerebellar nuclei and Purkinje cells,as well as the number of neuronal intranuclear inclusions and neurons.Laboratory should value the use of existing MJD/SCA3 animal models or the production of new animal models to find the new therapeutic targets from the aspects of postponing the disease occurrence,delaying the progress of the disease,clearing the neuronal intranuclear inclusions and extending the life span.