<EM>CREB3<SUP>R119G</SUP></EM> DRIVES NEURONAL RESILIENCE IN AMYOTROPHIC LATERAL SCLEROSIS

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by the loss of glutamatergic corticospinal neurons (CSN) and cholinergic neurons (MN). It results in muscular weakness, fasciculations and atrophy that eventually lead to respiratory failure. It is mostly sporadic in 90% of cases, but genetics is expected to highly contribute to disease onset and progression. Indeed, genome-wide association studies (GWAS) identified a few genetic disease modifiers, mostly associated with a negative outcome, and demonstrated that ALS is primarily a disease of excitatory glutamatergic neurons. Using comparative cross-species single-cell transcriptomics from mouse models and human ALS patients, we formerly showed that disease-vulnerable neuronal populations undergo ER stress and altered mRNA translation. Importantly, we identified the transcription factor CREB3 (Cyclic AMP-Responsive Element-Binding Protein 3) and its regulatory network as a resilience marker of neuronal dysfunction in ALS. Through genetic and epidemiologic analyses, we further identified the rare variant CREB3^R119G (rs11538707) as a new disease modifier in ALS that decreases both the risk of developing ALS and the progression rate of ALS patients. Our project now aims at determining the mechanisms of neuronal resilience activated by CREB3^R119G. To this end, we started characterizing the molecular signature of induced pluripotent stem cells (iPSC) and iPSC-derived motor neurons (iPSC-MN) harboring a homozygous insertion of the R119G variant. We sought to combine multi-omics approaches (RNAseq, CUT&TAG, mass spectrometry) to identify the molecular pathways selectively activated by the variant proteins, in presence and absence of disease-relevant cellular stressors, and tie the latter to TDP-43 function.