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）是一类遗传异质性的遗传性多发性神经病，可引发周围神经系统轴突变性。2D型夏科-马里-图思神经病（CMT2D）由甘氨酰-tRNA合成酶（Glycyl tRNA synthetase, GARS）的显性突变所致。小鼠Gars基因的突变可构建出遗传学与表型层面均验证有效的CMT2D动物模型。目前，GARS突变引发周围神经病的具体机制仍存在争议。
为探究潜在的致病机制，本研究对Gars突变小鼠及其同窝对照小鼠脊髓中提取的代谢物进行了对比分析，最终得到了可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（Ascorbic acid）水平下调四倍，但其血清中的该物质水平未发生改变；突变小鼠脊髓组织中的肉碱及其衍生物水平也显著降低，而甘氨酸水平则有所升高。
膳食补充乙酰-L-肉碱（acetyl-L-carnitine）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病变的相关参数。本研究通过临床血液生化检测，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，证实上述代谢变化并非继发于神经肌肉表型。然而，这些变化似乎并非CMT2D的致病性或一致性代谢特征，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”有助于加深我们对GARS突变相关细胞生化改变的认识，但要确定有效的治疗策略并阐明该病的致病机制，仍需开展进一步研究。