Unexpected phenotypic and molecular changes of combined glucocerebrosidase and acid sphingomyelinase deficiency.
Unexpected phenotypic and molecular changes of combined glucocerebrosidase and acid sphingomyelinase deficiency.
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DOI：
10.1242/dmm.049954
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发表时间：
2023-06-01
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
--
作者：
GBA1编码葡萄糖脑苷脂酶（GCase）的杂合变体是帕金森病（PD）最常见的遗传风险因素。此外，散发性PD患者也具有GCase活性的显著降低。SMPD 1的遗传变异在PD队列中也有过高的表现，而其编码的酶（酸性鞘磷脂酶或ASM）活性的降低与PD发病年龄的提前有关。尽管两者都集中在神经酰胺途径上，但两种酶的组合缺陷如何相互作用以调节PD尚未被探索。因此，我们创建了一个双敲除（DKO）斑马鱼线的gba 1（或gba）和smpd1测试在体内的相互作用，假设恶化的表型相比，单突变体的DKO线。出乎意料的是，DKO斑马鱼保持了传统的游泳行为，并且与单一突变体相比具有正常化的神经元基因表达特征。我们进一步鉴定了DKO斑马鱼中线粒体复合物I和IV的拯救。尽管有一个意想不到的救援效果，我们的研究结果证实ASM作为GBA 1缺乏症在体内的修饰剂。我们的研究强调了验证遗传变异和酶缺陷如何在体内相互作用的必要性。总结：同时抑制gba1和smpd1基因功能（均与帕金森病有关）意外地挽救了神经元基因表达和线粒体缺陷，并延长了gba1突变斑马鱼的寿命。
Heterozygous variants in GBA1, encoding glucocerebrosidase (GCase), are the most common genetic risk factor for Parkinson's disease (PD). Moreover, sporadic PD patients also have a substantial reduction of GCase activity. Genetic variants of SMPD1 are also overrepresented in PD cohorts, whereas a reduction of its encoded enzyme (acid sphingomyelinase or ASM) activity is linked to an earlier age of PD onset. Despite both converging on the ceramide pathway, how the combined deficiencies of both enzymes might interact to modulate PD has yet to be explored. Therefore, we created a double-knockout (DKO) zebrafish line for both gba1 (or gba) and smpd1 to test for an interaction in vivo, hypothesising an exacerbation of phenotypes in the DKO line compared to those for single mutants. Unexpectedly, DKO zebrafish maintained conventional swimming behaviour and had normalised neuronal gene expression signatures compared to those of single mutants. We further identified rescue of mitochondrial Complexes I and IV in DKO zebrafish. Despite having an unexpected rescue effect, our results confirm ASM as a modifier of GBA1 deficiency in vivo. Our study highlights the need for validating how genetic variants and enzymatic deficiencies may interact in vivo. Summary: Simultaneous inhibition of gba1 and smpd1 gene function (both implicated in Parkinson's disease) unexpectedly rescues neuronal gene expression and mitochondrial defects, and extends the lifespan of gba1 mutant zebrafish.
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影响因子：
9
作者：
Gillmore T;Farrell A;Alahari S;Sallais J;Kurt M;Park C;Ausman J;Litvack M;Post M;Caniggia I
通讯作者：
Caniggia I
影响因子：
4.5
作者：
Keatinge M;Tsarouchas TM;Munir T;Porter NJ;Larraz J;Gianni D;Tsai HH;Becker CG;Lyons DA;Becker T
通讯作者：
Becker T
影响因子：
13.5
作者：
Canals, Daniel;Clarke, Christopher J.
通讯作者：
Clarke, Christopher J.
影响因子：
6.5
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.
通讯作者：
Aerts, Johannes M. F. G.
影响因子：
14.5
作者：
Neumann, Juliane;Bras, Jose;Wood, Nicholas W.
通讯作者：
Wood, Nicholas W.