Disruption of ribosome dynamics and mRNA homeostasis triggers a cascading imbalance in protein synthesis in models of Amyotrophic Lateral Sclerosis

The RNA-binding protein TDP-43 is a major contributor and a pathological hallmark of Amyotrophic Lateral Sclerosis (ALS), yet how TDP-43 dysregulation mechanistically alters protein synthesis across neuronal compartments and disease models remains unclear. Here, we dissected TDP-43-driven translational alterations in both in vitro and in vivo TDP-43 models of ALS. Through ribosome and polysome profiling, computational, and biochemical analyses, we observed robust TDP-43-associated translational remodelling at cellular and subcellular resolution. Our findings reveal a conserved mechanism across models, characterized by enhanced ribosome recruitment on polysomes, elongation impairment, axonal downregulation and instability of TDP-43 target mRNAs and redistribution toward non-target transcripts. Notably, TDP-43 dysregulation alters ribosome dynamics and selectively impairs translation of TDP-43 target mRNAs, whilst favouring the translation of other transcripts. This process reflects a compensatory but maladaptive response to TDP-43-induced mRNA destabilization. Together, these data demonstrate that alterations in TDP-43 disrupts neuronal proteostasis through ribosome reorganization and loss of mRNA homeostasis, providing a unifying mechanistic framework for translational imbalance in ALS and revealing early molecular events that may underlie motor neuron vulnerability.