Elevated glutaric acid levels in Dhtkd1-/Gcdh- double knockout mice challenge our current understanding of lysine metabolism
Elevated glutaric acid levels in Dhtkd1-/Gcdh- double knockout mice challenge our current understanding of lysine metabolism
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DOI：
10.1016/j.bbadis.2017.05.018
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发表时间：
2017-09-01
影响因子：
6.2
通讯作者：
Prokisch, Holger
中科院分区：
文献类型：
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作者：
Biagosch, Caroline;Ediga, Raga Deepthi;Prokisch, Holger
I 型戊二酸尿症 (GA-I) 是一种罕见的有机酸尿症，由常染色体隐性遗传的戊二酰辅酶 A 脱氢酶 (GCDH) 缺陷引起。 GCDH 缺乏会导致 L-赖氨酸降解中断，并导致戊二酰肉碱和神经毒性戊二酸 (GA)、戊二酰辅酶 A、3-羟基戊二酸 (3-OHGA) 的特征性积累。 DHTKD1 作用于 GCDH 的上游，其缺陷不会导致人类临床表型，或通常导致轻微的临床表型，即 2-氨基己二酸 2-氧代己二酸尿症。我们假设抑制 DHTKD1 可能会阻止神经毒性二羧酸代谢物的积累，这表明 DHTKD1 抑制是 GA-I 的一种可能的治疗策略。为了验证这一假设，我们利用现有的 GA-I (Gcdh(-) (/) (-)) 小鼠模型，建立了 Dhtkdl 缺陷小鼠模型。两种模型都再现了在患者中观察到的生化和临床表型。在高赖氨酸饮食的挑战性条件下，只有 Gcdh(-) (/) (-) 小鼠而不是 Dhtkdl(-) (/) (-) 小鼠出现昏睡行为和体重减轻等临床症状。然而，Dhtlall(-)(/)(-)/Gcdh(-)(/)(-)小鼠中的遗传Dhtkdl抑制不能挽救GA-I表型。生化结果证实了这一发现，双基因敲除小鼠显示出与大脑和肝脏中高 GA 的 Gcdh(-) (/) (-) 小鼠相似的代谢物积累。这表明单独抑制 DHTKD1 不足以治疗 GA-I，而是需要更复杂的策略。我们的数据强调了 L-赖氨酸降解途径中许多未解决的问题，并为迄今为止未知的导致戊二酰辅酶A的机制提供了证据。
Glutaric aciduria type I (GA-I) is a rare organic aciduria caused by the autosomal recessive inherited deficiency of glutaryl-CoA dehydrogenase (GCDH). GCDH deficiency leads to disruption of L-lysine degradation with characteristic accumulation of glutarylcarnitine and neurotoxic glutaric acid (GA), glutaryl-CoA, 3-hydroxyglutaric acid (3-OHGA). DHTKD1 acts upstream of GCDH, and its deficiency leads to none or often mild clinical phenotype in humans, 2-aminoadipic 2-oxoadipic aciduria. We hypothesized that inhibition of DHTKD1 may prevent the accumulation of neurotoxic dicarboxylic metabolites suggesting DHTKD1 inhibition as a possible treatment strategy for GA-I. In order to validate this hypothesis we took advantage of an existing GA-I (Gcdh(-) (/) (-)) mouse model and established a Dhtkdl deficient mouse model. Both models reproduced the biochemical and clinical phenotype observed in patients. Under challenging conditions of a high lysine diet, only Gcdh(-) (/) (-) mice but not Dhtkdl(-) (/) (-) mice developed clinical symptoms such as lethargic behaviour and weight loss. However, the genetic Dhtkdl inhibition in Dhtlall(-) (/) (-) /Gcdh(-) (/) (-) mice could not rescue the GA-I phenotype. Biochemical results confirm this finding with double knockout mice showing similar metabolite accumulations as Gcdh(-) (/) (-) mice with high GA in brain and liver. This suggests that DHTKD1 inhibition alone is not sufficient to treat GA-I, but instead a more complex strategy is needed. Our data highlights the many unresolved questions within the L-lysine degradation pathway and provides evidence for a so far unknown mechanism leading to glutaryl-CoA.