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 ...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（Charcot-Marie-Tooth type 2D neuropathy, 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符合CMT2D特征的有效动物模型。目前，GARS突变引发周围神经病的具体机制仍存在争议。为探明潜在的疾病发病机制，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，明确了可区分病变与正常组织的差异代谢物谱。夏科-马里-图思病小鼠脊髓内的抗坏血酸（ascorbic acid）水平较对照下降四倍，但血清中该物质未出现明显改变。肉碱（carnitine）及其衍生物在突变小鼠脊髓组织中同样显著减少，而甘氨酸水平则有所升高。经乙酰-L-肉碱（acetyl-L-carnitine）膳食补充后，症状得到改善。