Aggregation chimeras provide evidence of in vivo intercellular correction in ovine CLN6 neuronal ceroid lipofuscinosis (Batten disease).
Aggregation chimeras provide evidence of in vivo intercellular correction in ovine CLN6 neuronal ceroid lipofuscinosis (Batten disease).
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DOI：
10.1371/journal.pone.0261544
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
神经元蜡样脂褐质沉积症（NCL；Batten 病）是致命的，主要是儿童遗传性神经退行性溶酶体贮积病。受到 CLN6 形式影响的绵羊表现出进行性区域限定的神经胶质激活和随后的神经变性，表明神经炎症可能是发病机制的原因。在这项研究中，聚集嵌合体是从纯合的未受影响的正常绵羊胚胎和CLN6受影响的绵羊胚胎中产生的，产生了七只嵌合动物，其正常细胞与受影响细胞的比例不同。根据细胞基因型比率及其临床和神经病理学特征，这些羊被分为受影响样、恢复样或正常样。对受影响动物的神经病理学检查显示，所有皮质脑区域内都有强烈的神经胶质激活、显着的存储体积累和严重的神经变性，以及视力丧失、颅内容量和皮质厚度减少，这与绵羊 CLN6 疾病一致。相比之下，在正常样和恢复样嵌合体中，影响病理学的细胞间通讯在总体和组织学水平上都很明显，导致仅少数细胞缺乏神经胶质活化和罕见的储存体积累。恢复样嵌合体的初始颅内容积低于正常水平，但到两岁时逐渐恢复到正常水平。所有人的皮质厚度都正常，没有人失明。所有嵌合体的大脑中都明显存在延长的神经发生。这项研究表明，尽管 CLN6 是一种膜结合蛋白，但随之而来的缺陷并不是细胞固有的。正常样和恢复样嵌合体中缺乏神经胶质活化和炎症反应，表明新生成的细胞处于有利于成熟和存活的微环境中。
The neuronal ceroid lipofuscinoses (NCLs; Batten disease) are fatal, mainly childhood, inherited neurodegenerative lysosomal storage diseases. Sheep affected with a CLN6 form display progressive regionally defined glial activation and subsequent neurodegeneration, indicating that neuroinflammation may be causative of pathogenesis. In this study, aggregation chimeras were generated from homozygous unaffected normal and CLN6 affected sheep embryos, resulting in seven chimeric animals with varied proportions of normal to affected cells. These sheep were classified as affected-like, recovering-like or normal-like, based on their cell-genotype ratios and their clinical and neuropathological profiles. Neuropathological examination of the affected-like animals revealed intense glial activation, prominent storage body accumulation and severe neurodegeneration within all cortical brain regions, along with vision loss and decreasing intracranial volumes and cortical thicknesses consistent with ovine CLN6 disease. In contrast, intercellular communication affecting pathology was evident at both the gross and histological level in the normal-like and recovering-like chimeras, resulting in a lack of glial activation and rare storage body accumulation in only a few cells. Initial intracranial volumes of the recovering-like chimeras were below normal but progressively recovered to about normal by two years of age. All had normal cortical thicknesses, and none went blind. Extended neurogenesis was evident in the brains of all the chimeras. This study indicates that although CLN6 is a membrane bound protein, the consequent defect is not cell intrinsic. The lack of glial activation and inflammatory responses in the normal-like and recovering-like chimeras indicate that newly generated cells are borne into a microenvironment conducive to maturation and survival.
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