Neurobiología Celular y Molecular, IIBCE, CIP 11600, Montevideo, Uruguay.
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, CEP 900035-003, Brazil.
Mol Neurobiol. 2019 Jan;56(1):648-657. doi: 10.1007/s12035-018-1077-x. Epub 2018 May 19.
Glutaric acidemia type I (GA-I) is a neurometabolic disease caused by deficient activity of glutaryl-CoA dehydrogenase (GCDH) that results in accumulation of metabolites derived from lysine (Lys), hydroxylysine, and tryptophan catabolism. GA-I patients typically develop encephalopatic crises with striatal degeneration and progressive white matter defects. However, late onset patients as well as Gcdh-/- mice only suffer diffuse myelinopathy, suggesting that neuronal death and white matter defects are different pathophysiological events. To test this hypothesis, striatal myelin was studied in Gcdh-/- mice fed from 30 days of age during up to 60 days with a diet containing normal or moderately increased amounts of Lys (2.8%), which ensure sustained elevated levels of GA-I metabolites. Gcdh-/- mice fed with 2.8% Lys diet showed a significant decrease in striatal-myelinated areas and progressive vacuolation of white matter tracts, as compared with animals fed with normal diet. Myelin pathology increased with the time of exposure to high Lys diet and was also detected in 90-day old Gcdh-/- mice fed with normal diet, suggesting that dietary Lys accelerated the undergoing white matter damage. Gcdh-/- mice fed with 2.8% Lys diet also showed increased GRP78/BiP immunoreactivity in oligodendrocytes and neurons, denoting ER stress. However, the striatal and cortical neuronal density was unchanged with respect to normal diet. Thus, myelin damage seen in Gcdh-/- mice fed with 2.8% Lys seems to be mediated by a long-term increased levels of GA-I metabolites having deleterious effects in myelinating oligodendrocytes over neurons.
I 型戊二酸血症（GA-I）是一种神经代谢疾病，由谷氨酰辅酶 A 脱氢酶（GCDH）活性缺乏引起，导致赖氨酸（Lys）、羟赖氨酸和色氨酸分解代谢的代谢物积累。GA-I 患者通常会出现伴有纹状体变性和进行性白质缺陷的脑病危象。然而，迟发性患者和 Gcdh-/- 小鼠仅患有弥漫性脱髓鞘病变，这表明神经元死亡和白质缺陷是不同的病理生理事件。为了验证这一假说，研究人员在 30 天大的 Gcdh-/- 小鼠中进行了研究，这些小鼠在 60 天的时间内食用含有正常或适度增加 Lys（2.8%）的饮食，以确保持续升高的 GA-I 代谢物水平。与正常饮食组相比，食用 2.8% Lys 饮食的 Gcdh-/- 小鼠纹状体髓鞘区域明显减少，白质束出现进行性空泡化。与正常饮食组相比，喂食正常饮食的 90 天大的 Gcdh-/- 小鼠的髓鞘病变也有所增加，这表明饮食 Lys 加速了正在进行的白质损伤。喂食 2.8% Lys 饮食的 Gcdh-/- 小鼠的少突胶质细胞和神经元中 GRP78/BiP 免疫反应性也增加，表明内质网应激。然而，与正常饮食相比，纹状体和皮质神经元密度没有变化。因此，喂食 2.8% Lys 的 Gcdh-/- 小鼠的髓鞘损伤似乎是由长期升高的 GA-I 代谢物水平介导的，这些代谢物对髓鞘形成的少突胶质细胞具有有害影响，而对神经元没有影响。
