脑内GABA代谢不足导致星形胶质细胞和少突胶质细胞功能广泛受损

Deficient brain GABA metabolism leads to widespread impairments of astrocyte and oligodendrocyte function

神经代谢障碍性疾病琥珀酸半醛脱氢酶(SSADH)缺乏症会导致严重的神经化学失衡和严重的神经表现。该病的病因是SSADH酶功能丧失,导致主要抑制性神经递质γ-氨基丁酸(GABA)代谢受损。尽管已知酶缺乏的身份,但SSADH缺乏症的潜在病理机制仍不清楚。为了揭示该病的新机制,我们在SSADH缺乏症的遗传小鼠模型(ALDH5A1基因敲除小鼠)中进行了脑蛋白表达、功能代谢和脂质组成的非靶向整合分析。我们的蛋白质组学分析显示存在明显的区域脆弱性,因为蛋白质改变主要在ALDH5A1基因敲除小鼠的海马体和大脑皮质中表现出来。这些区域显示出与氨基酸稳态、线粒体、胶质细胞功能和髓鞘形成相关的蛋白质异常表达。在急性分离的脑切片中进行稳定同位素示踪显示,葡萄糖的氧化代谢总体上得以维持,但ALDH5A1基因敲除小鼠大脑皮质的星形胶质细胞代谢活性有所下降。相比之下,在ALDH5A1基因敲除小鼠的大脑中观察到氧化性谷氨酰胺代谢能力增强,这可能是星形胶质细胞谷氨酰胺供应受损的神经元补偿。除了少突胶质细胞关键蛋白表达减少外,ALDH5A1基因敲除小鼠大脑中还发现富含髓鞘的神经鞘脂严重耗竭,表明髓鞘退化。综上所述,我们的研究表明星形胶质细胞和少突胶质细胞功能障碍与SSADH缺乏症病理密切相关,提示选择性靶向胶质细胞可能在该病的治疗中具有潜力。

The neurometabolic disorder succinic semialdehyde dehydrogenase(SSADH)deficiency leads to great neurochemical imbalances and severe neurological manifestations.The cause of the disease is loss of function of the enzyme SSADH,leading to impaired metabolism of the principal inhibitory neurotransmitter GABA.Despite the known identity of the enzymatic deficit,the underlying pathology of SSADH deficiency remains unclear.To uncov-er new mechanisms of the disease,we performed an untargeted integrative analysis of cerebral protein expression,functional metabolism,and lipid composition in a genetic mouse model of SSADH deficiency(ALDH5A1 knockout mice).Our proteomic analysis revealed a clear regional vulnerability,as protein alterations primarily manifested in the hippocampus and cerebral cortex of the ALDH5A1 knockout mice.These regions displayed aberrant expression of proteins linked to amino acid homeostasis,mitochondria,glial function,and myelination.Stable isotope tracing in acutely isolated brain slices demonstrated an overall maintained oxidative metabolism of glucose,but a selective de-crease in astrocyte metabolic activity in the cerebral cortex of ALDH5A1 knockout mice.In contrast,an elevated ca-pacity of oxidative glutamine metabolism was observed in the ALDH5A1 knockout brain,which may serve as a neu-ronal compensation of impaired astrocyte glutamine provision.In addition to reduced expression of critical oligoden-drocyte proteins,a severe depletion of myelin-enriched sphingolipids was found in the brains of ALDH5A1 knock-out mice,suggesting degeneration of myelin.Altogether,our study highlights that impaired astrocyte and oligoden-drocyte function is intimately linked to SSADH deficiency pathology,suggesting that selective targeting of glial cells may hold therapeutic potential in this disease.