Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development.,Glia

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Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development.
Glia ( IF 5.4 ) Pub Date : 2019-05-29 , DOI: 10.1002/glia.23641
Laura E Kuil ₁ , Anna López Martí ₁ , Ana Carreras Mascaro ₁ , Jeroen C van den Bosch ₁ , Paul van den Berg ₁ , Herma C van der Linde ₁ , Kees Schoonderwoerd ₁ , George J G Ruijter ₁ , Tjakko J van Ham ₁

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Sphingolipidoses are severe, mostly infantile lysosomal storage disorders (LSDs) caused by defective glycosphingolipid degradation. Two of these sphingolipidoses, Tay Sachs and Sandhoff diseases, are caused by β-Hexosaminidase (HEXB) enzyme deficiency, resulting in ganglioside (GM2) accumulation and neuronal loss. The precise sequence of cellular events preceding, and leading to, neuropathology remains unclear, but likely involves inflammation and lysosomal accumulation of GM2 in multiple cell types. We aimed to determine the consequences of Hexb activity loss for different brain cell types using zebrafish. Hexb deficient zebrafish (hexb-/- ) showed lysosomal abnormalities already early in development both in radial glia, which are the neuronal and glial progenitors, and in microglia. Additionally, at 5 days postfertilization, hexb-/- zebrafish showed reduced locomotor activity. Although specific oligosaccharides accumulate in the adult brain, hexb-/- ) zebrafish are viable and apparently resistant to Hexb deficiency. In all, we identified cellular consequences of loss of Hexb enzyme activity during embryonic brain development, showing early effects on glia, which possibly underlie the behavioral aberrations. Hereby, we identified clues into the contribution of non-neuronal lysosomal abnormalities in LSDs affecting the brain and provide a tool to further study what underlies the relative resistance to Hexb deficiency in vivo.

中文翻译：

Hexb 酶缺乏会导致斑马鱼大脑发育中放射状胶质细胞和小胶质细胞的溶酶体异常。

鞘脂沉积症是一种严重的疾病，主要是由鞘糖脂降解缺陷引起的婴儿溶酶体贮积症 (LSD)。其中两种鞘脂沉积症（Tay Sachs 病和 Sandhoff 病）是由 β-己糖胺酶 (HEXB) 酶缺乏引起的，导致神经节苷脂 (GM2) 积累和神经元损失。神经病理学之前和导致神经病理学的细胞事件的精确顺序仍不清楚，但可能涉及炎症和多种细胞类型中 GM2 的溶酶体积累。我们的目的是利用斑马鱼确定 Hexb 活性丧失对不同脑细胞类型的影响。Hexb 缺陷斑马鱼 (hexb-/- ) 在放射状胶质细胞（神经元和神经胶质祖细胞）和小胶质细胞的发育早期就表现出溶酶体异常。此外，受精后 5 天，hexb-/- 斑马鱼表现出运动活性降低。尽管特定的寡糖在成年大脑中积聚，但 hexb-/- ) 斑马鱼仍能存活，并且对 Hexb 缺乏症具有明显的抵抗力。总之，我们确定了胚胎大脑发育过程中 Hexb 酶活性丧失的细胞后果，显示出对神经胶质细胞的早期影响，这可能是行为异常的基础。因此，我们确定了影响大脑的 LSD 中非神经元溶酶体异常的线索，并提供了进一步研究体内对 Hexb 缺乏的相对抵抗力的基础的工具。

更新日期：2019-05-29

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