Consequences of excessive glucosylsphingosine in glucocerebrosidase-deficient zebrafish.
Consequences of excessive glucosylsphingosine in glucocerebrosidase-deficient zebrafish.
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DOI：
10.1016/j.jlr.2022.100199
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发表时间：
2022-05
影响因子：
6.5
通讯作者：
Aerts, Johannes M. F. G.
中科院分区：
文献类型：
--
作者：
Lelieveld, Lindsey T.;Gerhardt, Sophie;Maas, Saskia;Zwiers, Kimberley C.;de Wit, Claire;Beijk, Ernst H.;Ferraz, Maria J.;Artola, Marta;Meijer, Annemarie H.;Tudorache, Christian;Salvatori, Daniela;Boot, Rolf G.;Aerts, Johannes M. F. G.
关键词：
在戈谢病（GD）中，葡萄糖脑苷酶的缺乏导致溶酶体中葡萄糖神经酰胺（GlcCer）的积累，部分由酸性神经酰胺酶在溶酶体中转化为葡萄糖神经酰胺（GlcSph）。长期升高的血液和组织GlcSph被认为有助于GD患者的症状以及帕金森病的风险增加。另一方面，GlcSph的形成可能是有益的，因为水溶性鞘碱通过尿液和胆汁排泄。为了研究葡萄糖脑苷酶缺乏时过量GlcSph形成的作用，我们研究了具有酸性神经酰胺酶Asah1a和Asah1b两个同源物的斑马鱼。只有后者参与糖脑苷酶缺陷斑马鱼中GlcSph的形成，这是通过敲除糖脑苷酶缺陷（药物诱导或遗传）的Asah1a或Asah1b所揭示的。比较GlcSph过量的斑马鱼（gba1-/- fish）和没有GlcSph的斑马鱼（gba1-/-:asah1b-/- fish）使我们能够研究慢性高水平GlcSph的后果。预防gba1-/-:asah1b-/-鱼体内过量的GlcSph并不会限制储存细胞、glcer积累或神经炎症。然而，缺乏过量GlcSph的GD鱼表现出改善的病程，表现为显著延长寿命，延迟运动异常和延迟异常弯曲背部姿势的发展。多巴胺能神经元的标志物酪氨酸羟化酶1 (th1) mRNA的丢失在缺乏过量GlcSph的GD鱼脑中减慢。综上所述，在斑马鱼GD模型中，过量的GlcSph对（神经）炎症或glccer巨噬细胞的存在几乎没有影响，但似乎对1阳性多巴胺能神经元有害。
In Gaucher disease (GD), the deficiency of glucocerebrosidase causes lysosomal accumulation of glucosylceramide (GlcCer), which is partly converted by acid ceramidase to glucosylsphingosine (GlcSph) in the lysosome. Chronically elevated blood and tissue GlcSph is thought to contribute to symptoms in GD patients as well as to increased risk for Parkinson’s disease. On the other hand, formation of GlcSph may be beneficial since the water soluble sphingoid base is excreted via urine and bile. To study the role of excessive GlcSph formation during glucocerebrosidase deficiency, we studied zebrafish that have two orthologs of acid ceramidase, Asah1a and Asah1b. Only the latter is involved in the formation of GlcSph in glucocerebrosidase-deficient zebrafish as revealed by knockouts of Asah1a or Asah1b with glucocerebrosidase deficiency (either pharmacologically induced or genetic). Comparison of zebrafish with excessive GlcSph (gba1-/- fish) and without GlcSph (gba1-/-:asah1b-/- fish) allowed us to study the consequences of chronic high levels of GlcSph. Prevention of excessive GlcSph in gba1-/-:asah1b-/- fish did not restrict storage cells, GlcCer accumulation, or neuroinflammation. However, GD fish lacking excessive GlcSph show an ameliorated course of disease reflected by significantly increased lifespan, delayed locomotor abnormality, and delayed development of an abnormal curved back posture. The loss of tyrosine hydroxylase 1 (th1) mRNA, a marker of dopaminergic neurons, is slowed down in brain of GD fish lacking excessive GlcSph. In conclusion, in the zebrafish GD model, excess GlcSph has little impact on (neuro)inflammation or the presence of GlcCer-laden macrophages but rather seems harmful to th1-positive dopaminergic neurons.
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影响因子：
4.6
作者：
Harjula SE;Ojanen MJT;Taavitsainen S;Nykter M;Rämet M
通讯作者：
Rämet M
影响因子：
2.3
作者：
Deegan, PB;Moran, MT;Cox, TM
通讯作者：
Cox, TM
影响因子：
1.9
作者：
Kinoshita, Shunsuke;Biswas, Gouranga;Sakai, Masahiro
通讯作者：
Sakai, Masahiro
影响因子：
4.8
作者：
BERNARDO, K;HURWITZ, R;SANDHOFF, K
通讯作者：
SANDHOFF, K
DOI：
10.1073/pnas.0708086104
发表时间：
2007-10-30
影响因子：
11.1
作者：
Enquist, Ida Berglin;Lo Bianco, Christophe;Karlsson, Stefan
通讯作者：
Karlsson, Stefan