Division of Child Neurology, University Children's Hospital Zurich, Zurich, Switzerland.
CRC Clinical Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
J Inherit Metab Dis. 2019 Jul;42(4):620-628. doi: 10.1002/jimd.12076. Epub 2019 Apr 15.
Deficiency of antiquitin (ATQ), an enzyme involved in lysine degradation, is the major cause of vitamin B -dependent epilepsy. Accumulation of the potentially neurotoxic α-aminoadipic semialdehyde (AASA) may contribute to frequently associated developmental delay. AASA is formed by α-aminoadipic semialdehyde synthase (AASS) via the saccharopine pathway of lysine degradation, or, as has been postulated, by the pipecolic acid (PA) pathway, and then converted to α-aminoadipic acid by ATQ. The PA pathway has been considered to be the predominant pathway of lysine degradation in mammalian brain; however, this was refuted by recent studies in mouse. Consequently, inhibition of AASS was proposed as a potential new treatment option for ATQ deficiency. It is therefore of utmost importance to determine whether the saccharopine pathway is also predominant in human brain cells. The route of lysine degradation was analyzed by isotopic tracing studies in cultured human astrocytes, ReNcell CX human neuronal progenitor cells and human fibroblasts, and expression of enzymes of the two lysine degradation pathways was determined by Western blot. Lysine degradation was only detected through the saccharopine pathway in all cell types studied. The enrichment of N-glutamate as a side product of AASA formation through AASS furthermore demonstrated activity of the saccharopine pathway. We provide first evidence that the saccharopine pathway is the major route of lysine degradation in cultured human brain cells. These results support inhibition of the saccharopine pathway as a new treatment option for ATQ deficiency.
抗坏血酸缺乏症（ATQ）是一种参与赖氨酸降解的酶，是维生素 B 依赖性癫痫的主要原因。潜在神经毒性的α-氨基己二酸半醛（AASA）的积累可能导致经常伴随的发育迟缓。AASA 是由赖氨酸降解的 saccharopine 途径中的α-氨基己二酸半醛合酶（AASS）形成的，或者如假设的那样，由哌啶酸（PA）途径形成，然后由 ATQ 转化为α-氨基己二酸。PA 途径被认为是哺乳动物大脑中赖氨酸降解的主要途径；然而，最近在小鼠中的研究对此提出了质疑。因此，抑制 AASS 被提议作为 ATQ 缺乏症的潜在新治疗选择。因此，确定 saccharopine 途径是否也是人脑细胞中主要途径至关重要。通过在培养的人星形胶质细胞、ReNcell CX 人神经祖细胞和人成纤维细胞中进行同位素示踪研究分析赖氨酸降解途径，并通过 Western blot 确定两种赖氨酸降解途径的酶的表达。在所有研究的细胞类型中，赖氨酸降解仅通过 saccharopine 途径检测到。AASA 形成过程中 N-谷氨酸作为副产物的富集进一步证明了 saccharopine 途径的活性。我们提供了第一个证据，证明 saccharopine 途径是培养的人脑细胞中赖氨酸降解的主要途径。这些结果支持抑制 saccharopine 途径作为 ATQ 缺乏症的新治疗选择。
