Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease arising from the degeneration of corticospinal neurons (CSN) and motoneurons. While ALS mostly affects adult individuals, juvenile forms exist that suggest that at least a subset of cases might arise from neurodevelopmental impairment. In the Sod1G86R mouse model of ALS, we formerly demonstrated that the developmental absence of CSN was beneficial, suggesting an abnormal development of this disease-relevant neuronal population. Neurodevelopmental and neurodegenerative diseases share common mechanisms including alterations in one-carbon metabolism (1Cmet), which is central to purine synthesis and proliferation, and to methylation and epigenetic regulations. To test the contribution of 1Cmet to CNS development in the context of ALS, we started characterizing 1Cmet in the developing and adult CSN from two mouse models of ALS, Sod1G86R and Fus+/∆NLS mice, employing a combination of transcriptomics, metabolomics and epigenetics. Using RNAscope and RNAseq, we investigated the expression patterns of the four key enzymes of 1Cmet: Dfhr, Mthfr, Mt2a and Ahcy. We observed that Dhfr expression was significantly decreased in cortical progenitors of both ALS mouse models compared to controls. In adult Sod1G86R CSN, we observed significant downregulation of Mthfr and upregulation of Ahcy, compared to control CSN. Work is ongoing to unravel the metabolomic and epigenetic consequences of these alterations. Because 1Cmet strongly relies on diet, this project may not only inform on the consequences of ALS-related mutations, but also of developmental dietary restrictions on the development and long-term health of the motor system.