Data from: Metabolite profile of a mouse model of Charcot-Marie-Tooth type 2D neuropathy: implications for disease mechanisms and interventions

Charcot-Marie-Tooth disease encompasses a genetically heterogeneous class of heritable polyneuropathies that result in axonal degeneration in the peripheral nervous system. Charcot-Marie-Tooth type 2D neuropathy (CMT2D) is caused by dominant mutations in glycyl tRNA synthetase (GARS). Mutations in the mouse Gars gene result in a genetically and phenotypically valid animal model of CMT2D. How mutations in GARS lead to peripheral neuropathy remains controversial. To identify putative disease mechanisms, we compared metabolites isolated from the spinal cord of Gars mutant mice and their littermate controls. A profile of altered metabolites that distinguish the affected and unaffected tissue was determined. Ascorbic acid was decreased fourfold in the spinal cord of CMT2D mice, but was not altered in serum. Carnitine and its derivatives were also significantly reduced in spinal cord tissue of mutant mice, whereas glycine was elevated. Dietary supplementation with acetyl-L-carnitine improved gross motor performance of CMT2D mice, but neither acetyl-L-carnitine nor glycine supplementation altered the parameters directly assessing neuropathy. Other metabolite changes suggestive of liver and kidney dysfunction in the CMT2D mice were validated using clinical blood chemistry. These effects were not secondary to the neuromuscular phenotype, as determined by comparison with another, genetically unrelated mouse strain with similar neuromuscular dysfunction. However, these changes do not seem to be causative or consistent metabolites of CMT2D, because they were not observed in a second mouse Gars allele or in serum samples from CMT2D patients. Therefore, the metabolite 'fingerprint' we have identified for CMT2D improves our understanding of cellular biochemical changes associated with GARS mutations, but identification of efficacious treatment strategies and elucidation of the disease mechanism will require additional studies.夏科-马里-图思病（Charcot-Marie-Tooth disease，CMT）是一类具有遗传异质性的遗传性多发性神经病，可导致周围神经系统轴突变性。2D型夏科-马里-图思神经病（Charcot-Marie-Tooth type 2D neuropathy，CMT2D）由甘氨酰-tRNA合成酶（glycyl tRNA synthetase，GARS）的显性突变引发。小鼠Gars基因突变可构建出CMT2D的遗传与表型均验证有效的动物模型。目前，GARS突变如何导致周围神经病的机制仍存在争议。为探究潜在的致病机制，本研究对比了Gars突变小鼠及其同窝对照小鼠脊髓中分离得到的代谢物，确定了区分病变与正常组织的差异代谢物谱。研究发现，CMT2D小鼠脊髓中的抗坏血酸水平下降了四倍，但血清中未出现该变化；突变小鼠脊髓组织中的肉碱及其衍生物水平也显著降低，而甘氨酸水平则升高。膳食补充乙酰-L-肉碱可改善CMT2D小鼠的整体运动能力，但无论是乙酰-L-肉碱还是甘氨酸补充剂，均未改变直接评估神经病的相关参数。本研究通过临床血液生化验证了CMT2D小鼠中其他提示肝肾功能异常的代谢物变化。通过与另一种遗传背景无关但存在类似神经肌肉功能障碍的小鼠品系对比，证实这些效应并非继发于神经肌肉表型。但这些变化似乎并非CMT2D的致病或一致性代谢特征，因为在第二种小鼠Gars等位基因突变模型以及CMT2D患者的血清样本中均未观察到此类变化。因此，本研究鉴定的CMT2D代谢物“指纹谱”可加深我们对GARS突变相关细胞生化变化的理解，但要确定有效的治疗策略并阐明疾病机制，仍需开展更多研究。