The failure of microglia to digest developmental apoptotic cells contributes to the pathology of RNASET2-deficient leukoencephalopathy.
The failure of microglia to digest developmental apoptotic cells contributes to the pathology of RNASET2-deficient leukoencephalopathy.
复制标题
小胶质细胞消化发育凋亡细胞的失败有助于RNASET2缺陷型白细胞病的病理。
作者：
Hamilton N;Rutherford HA;Petts JJ;Isles HM;Weber T;Henneke M;Gärtner J;Dunning MJ;Renshaw SA
小胶质细胞在神经疾病中的作用正在成为主要的疾病驱动因素，而不是病理的结果。RNAseT2缺陷性白质脑病是一种严重的儿童脑白质疾病，影响患者生命的第一年，类似于巨细胞病毒脑感染。早期发病和类似病毒感染的症状提示炎症和胚胎起源的病理。目前还没有治疗这种疾病的方法，因为我们对病理的细胞驱动因素的了解仍然未知。在这项研究中，利用斑马鱼rnaset2基因的同源突变体，我们已经确定了早期发育中的炎症特征和成熟成人大脑中的抗病毒免疫反应。利用斑马鱼幼体的光学透明和体外发育，我们研究了脑发育过程中免疫细胞的行为，发现异常的小胶质细胞是早期的病理标志。活体成像和电子显微镜观察表明，突变的小胶质细胞形态饱满，充满未消化的凋亡细胞和未消化的底物。通过小胶质细胞特异性耗竭和挽救实验，我们确定小胶质细胞是这种胚胎表型的驱动因素，并在RNAseT2缺陷白质脑病的病理过程中发挥潜在的关键细胞作用。我们的斑马鱼模型也表现出存活率和运动缺陷的减少，因此概括了人类疾病的许多方面。因此，我们的研究将我们的rnaset2突变体置于白质营养不良临床前模型的前沿，并强调了组织特异性方法作为未来治疗途径。Rnaset2的缺失会导致炎症和溶酶体缺陷的小胶质细胞无法消化死亡的神经元。靶向小胶质细胞修复胚胎小胶质细胞缺陷以清除神经发育中的细胞凋亡。突变体减少了存活率和运动缺陷。
The contribution of microglia in neurological disorders is emerging as a leading disease driver rather than a consequence of pathology. RNAseT2‐deficient leukoencephalopathy is a severe childhood white matter disorder affecting patients in their first year of life and mimicking a cytomegalovirus brain infection. The early onset and resemblance of the symptoms to a viral infection suggest an inflammatory and embryonic origin of the pathology. There are no treatments available for this disease as our understanding of the cellular drivers of the pathology are still unknown. In this study, using a zebrafish mutant for the orthologous rnaset2 gene, we have identified an inflammatory signature in early development and an antiviral immune response in mature adult brains. Using the optical transparency and the ex utero development of the zebrafish larvae we studied immune cell behavior during brain development and identified abnormal microglia as an early marker of pathology. Live imaging and electron microscopy identified that mutant microglia displayed an engorged morphology and were filled with undigested apoptotic cells and undigested substrate. Using microglia‐specific depletion and rescue experiments, we identified microglia as drivers of this embryonic phenotype and potential key cellular player in the pathology of RNAseT2‐deficient leukoencephalopathy. Our zebrafish model also presented with reduced survival and locomotor defects, therefore recapitulating many aspects of the human disease. Our study therefore placed our rnaset2 mutant at the forefront of leukodystrophy preclinical models and highlighted tissue‐specific approaches as future therapeutic avenues. Loss of rnaset2 results in inflammation and lysosomal‐deficient microglia failing to digest dying neurons. Targeting microglia restores embryonic microglial defects to clear neurodevelopmental apoptosis. Mutants have reduced survival and locomotor defects.
登录
查看更多内容
影响因子：
4.2
作者：
Penati, Rachele;Fumagalli, Francesca;Aiuti, Alessandro
通讯作者：
Aiuti, Alessandro
影响因子：
56.9
作者：
FRATANTONI, JC;HALL, CW;NEUFELD, EF
通讯作者：
NEUFELD, EF
DOI：
10.1073/pnas.1009811107
发表时间：
2011-01-18
影响因子：
11.1
作者：
Haud, Noemie;Kara, Firat;Hurlstone, Adam F. L.
通讯作者：
Hurlstone, Adam F. L.
影响因子：
3.7
作者：
Arloth J;Bader DM;Röh S;Altmann A
通讯作者：
Altmann A
影响因子：
20.3
作者：
Li, Li;Jin, Hao;Wen, Zilong
通讯作者：
Wen, Zilong