Deletion of 2-aminoadipic semialdehyde synthase limits metabolite accumulation in cell and mouse models for glutaric aciduria type 1.,Journal of Inherited Metabolic Disease

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Deletion of 2-aminoadipic semialdehyde synthase limits metabolite accumulation in cell and mouse models for glutaric aciduria type 1.
Journal of Inherited Metabolic Disease ( IF 4.2 ) Pub Date : 2020-06-21 , DOI: 10.1002/jimd.12276
João Leandro _{1,

2} , Tetyana Dodatko _{1,

2} , Robert J DeVita _{3,

4} , Hongjie Chen _{1,

5} , Brandon Stauffer _{1,

5} , Chunli Yu _{1,

5} , Sander M Houten _{1,

2}

Affiliation

Glutaric aciduria type 1 (GA1) is an inborn error of lysine degradation characterized by acute encephalopathy that is caused by toxic accumulation of lysine degradation intermediates. We investigated the efficacy of substrate reduction through inhibition of 2‐aminoadipic semialdehyde synthase (AASS), an enzyme upstream of the defective glutaryl‐CoA dehydrogenase (GCDH), in a cell line and mouse model of GA1. We show that loss of AASS function in GCDH‐deficient HEK‐293 cells leads to an approximately fivefold reduction in the established GA1 clinical biomarker glutarylcarnitine. In the GA1 mouse model, deletion of Aass leads to a 4.3‐, 3.8‐, and 3.2‐fold decrease in the glutaric acid levels in urine, brain, and liver, respectively. Parallel decreases were observed in urine and brain 3‐hydroxyglutaric acid levels, and plasma, urine, and brain glutarylcarnitine levels. These in vivo data demonstrate that the saccharopine pathway is the main source of glutaric acid production in the brain and periphery of a mouse model for GA1, and support the notion that pharmacological inhibition of AASS may represent an attractive strategy to treat GA1.

中文翻译：

2-氨基己二酸半醛合酶的缺失限制了 1 型戊二酸尿症的细胞和小鼠模型中代谢物的积累。

1 型戊二酸尿症 (GA1) 是赖氨酸降解的先天性错误，其特征是由赖氨酸降解中间体的毒性积累引起的急性脑病。我们在 GA1 的细胞系和小鼠模型中研究了通过抑制 2-氨基己二酸半醛合酶 (AASS) 来减少底物的功效，该酶是缺陷型戊二酰辅酶 A 脱氢酶 (GCDH) 上游的一种酶。我们表明，GCDH 缺陷型 HEK-293 细胞中 AASS 功能的丧失导致已建立的 GA1 临床生物标志物戊二酰肉碱减少约五倍。在 GA1 小鼠模型中，删除Aass导致尿液、大脑和肝脏中戊二酸水平分别下降 4.3、3.8 和 3.2 倍。在尿液和大脑 3-羟基戊二酸水平以及血浆、尿液和大脑戊二酰肉碱水平中观察到平行下降。这些体内数据表明，糖碱途径是 GA1 小鼠模型大脑和外周中戊二酸产生的主要来源，并支持 AASS 的药理学抑制可能代表一种有吸引力的治疗 GA1 策略的观点。

更新日期：2020-06-21

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