Soerensen Jonna, Jakupoglu Cemile, Beck Heike, Förster Heidi, Schmidt Jörg, Schmahl Wolfgang, Schweizer Ulrich, Conrad Marcus, Brielmeier Markus
Department of Comparative Medicine, Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg, Germany.
PLoS One. 2008 Mar 19;3(3):e1813. doi: 10.1371/journal.pone.0001813.
The thioredoxin-dependent system is an essential regulator of cellular redox balance. Since oxidative stress has been linked with neurodegenerative disease, we studied the roles of thioredoxin reductases in brain using mice with nervous system (NS)-specific deletion of cytosolic (Txnrd1) and mitochondrial (Txnrd2) thioredoxin reductase. While NS-specific Txnrd2 null mice develop normally, mice lacking Txnrd1 in the NS were significantly smaller and displayed ataxia and tremor. A striking patterned cerebellar hypoplasia was observed. Proliferation of the external granular layer (EGL) was strongly reduced and fissure formation and laminar organisation of the cerebellar cortex was impaired in the rostral portion of the cerebellum. Purkinje cells were ectopically located and their dendrites stunted. The Bergmann glial network was disorganized and showed a pronounced reduction in fiber strength. Cerebellar hypoplasia did not result from increased apoptosis, but from decreased proliferation of granule cell precursors within the EGL. Of note, neuron-specific inactivation of Txnrd1 did not result in cerebellar hypoplasia, suggesting a vital role for Txnrd1 in Bergmann glia or neuronal precursor cells.
硫氧还蛋白依赖性系统是细胞氧化还原平衡的重要调节因子。由于氧化应激与神经退行性疾病有关，我们利用特异性敲除胞质（Txnrd1）和线粒体（Txnrd2）硫氧还蛋白还原酶的神经系统（NS）小鼠，研究了硫氧还蛋白还原酶在大脑中的作用。虽然NS特异性Txnrd2基因敲除小鼠发育正常，但NS中缺乏Txnrd1的小鼠明显更小，并表现出共济失调和震颤。观察到明显的小脑发育不全模式。小脑外部颗粒层（EGL）的增殖强烈减少，小脑皮质的裂隙形成和分层组织在小脑的前部受损。浦肯野细胞异位定位，其树突发育不良。伯格曼胶质细胞网络紊乱，纤维强度明显降低。小脑发育不全不是由细胞凋亡增加引起的，而是由EGL内颗粒细胞前体的增殖减少引起的。值得注意的是，Txnrd1的神经元特异性失活并未导致小脑发育不全，这表明Txnrd1在伯格曼胶质细胞或神经元前体细胞中起着至关重要的作用。
