Abstract
Charcot-Marie-Tooth Type 1 A (CMT1A) is a hereditary neuropathy caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. Emerging evidence suggests that lipid metabolism plays a central role in CMT1A pathology. This study investigated metabolic profiles in sciatic nerve tissue and plasma of PMP22 transgenic (TG) and wild-type (WT) rats at 2, 4, and 6 months of age. Utilizing targeted metabolomics, more than 600 metabolites covering central metabolic pathways and major lipid classes were analyzed, revealing distinct age-dependent changes in metabolic pathways. Alterations that emerged early and became increasingly pronounced with age were observed in sphingolipids and glycerophospholipids, while changes in other metabolic pathways, such as amino acids, storage lipids, bile acids, and nucleotide metabolism, were age-specific. Notably, in contrast to these age-dependent adaptive changes, three lipid signatures were identified that remained stable from the earliest age examined. These include: (1) an elevated ratio of hydroxylated to non-hydroxylated sphingolipids, (2) a reduced ratio of monounsaturated-containing to saturated fatty acid containing phosphatidylcholines, and (3) a decreased ratio of hexosylceramides to ceramides. Imaging mass spectrometry analyses confirmed disruptions in sphingolipid metabolism. These findings suggest a key regulatory role of PMP22 in lipid metabolism, as demonstrated by the early stabilization of specific lipid signatures compared to other metabolic changes that occurred in an age-dependent and adaptive manner. These observations provide valuable insights into the pathogenic mechanisms underlying CMT1A.