CORTICAL NEURONS ARE NEURODEVELOPMENTALLY PRIMED TO DYSFUNCTION AND DEGENERATION IN AMYOTROPHIC LATERAL SCLEROSIS MOUSE MODELS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of corticospinal neurons (CSN) and motoneurons. While ALS mostly affect adults, juvenile forms exist, suggesting that a subset of cases might originate from neurodevelopmental impairments. Using the Sod1^G86R mouse model of ALS, we previously demonstrated that the developmental absence of CSN was beneficial, pointing to abnormal development of this disease-relevant neuronal population. Neurodevelopmental and neurodegenerative diseases share common mechanisms including alterations in one-carbon metabolism (1Cmet), which is essential for DNA and purine synthesis and epigenetic regulation. Hence, this project investigates whether ALS may arise from neurodevelopmental impairments in 1Cmet, focusing on the motor cortex and CSN, using omics approaches in the genetically and phenotypically complementary Sod1^G86R and Fus^+/∆NLS mouse models. RNAscope analysis revealed a significant increase in Dhfr expression, a key folate cycle enzyme, in E13.5 cortical progenitors (CP) from both models. This increase is not associated with changes in proliferation, as densities of apical progenitors (PAX6+), intermediate progenitors (TBR2+), post-mitotic neurons (CTIP2+) and mitotic cells (PH3+) remain unchanged. However, FANS followed by DNA content analysis and BrdU labelling reveal a significant increase in the percentage of CP in S-phase and decrease in G1-phase indicating cell-cycle dysregulation. Cut&Tag profiling of H3K4me3 and H3K27me3 further supports cell-cycle dysregulation. Most importantly, we identified an epigenetic signature of altered synaptogenesis in CP of both ALS mouse models that is being validated. Together, these findings suggest that long before neurodegeneration onset, cortical neurons may be developmentally primed for dysfunction and vulnerability.