rnaset2 mutant zebrafish model familial cystic leukoencephalopathy and reveal a role for RNase T2 in degrading ribosomal RNA
rnaset2 mutant zebrafish model familial cystic leukoencephalopathy and reveal a role for RNase T2 in degrading ribosomal RNA
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DOI：
10.1073/pnas.1009811107
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发表时间：
2011-01-18
影响因子：
11.1
通讯作者：
Hurlstone, Adam F. L.
中科院分区：
文献类型：
--
作者：
Haud, Noemie;Kara, Firat;Hurlstone, Adam F. L.
T2 家族酸性核糖核酸内切酶存在于所有基因组中。 RNase T2 对于后生动物的生理作用尚未确定。人类的 RNASET2 突变与婴儿期出现的白质脑病有关，其特征是皮质囊肿和多灶性白质病变。我们现在展示 RNASET2 在溶酶体中的定位。此外，我们证明突变斑马鱼中 rnaset2 的缺失会导致大脑神经元内溶酶体内未消化的 rRNA 积累。此外，通过使用高场强度磁共振显微成像，我们揭示了这些动物的白质病变与在 RNASET2 缺陷婴儿中观察到的白质病变相当。这与淀粉样前体蛋白和星形胶质细胞在神经变性部位的积累相关。因此，我们得出结论，家族性囊性白质脑病是一种溶酶体贮积病，其中 rRNA 是有毒贮藏材料的最佳候选者。
T2-family acidic endoribonucleases are represented in all genomes. A physiological role for RNase T2 has yet to be defined for metazoa. RNASET2 mutation in humans is linked with a leukoencephalopathy that arises in infancy characterized by cortical cysts and multifocal white matter lesions. We now show localization of RNASET2 within lysosomes. Further, we demonstrate that loss of rnaset2 in mutant zebrafish results in accumulation of undigested rRNA within lysosomes within neurons of the brain. Further, by using high field intensity magnetic resonance microimaging, we reveal white matter lesions in these animals comparable to those observed in RNASET2-deficient infants. This correlates with accumulation of Amyloid precursor protein and astrocytes at sites of neurodegeneration. Thus we conclude that familial cystic leukoencephalopathy is a lysosomal storage disorder in which rRNA is the best candidate for the noxious storage material.