Protein Synthesis Dysregulation in Neurodegeneration: Mechanisms, Consequences, and Therapeutic Modulation.

Protein synthesis in neurons is essential for shaping and maintaining the proteome, which underpins synaptic function, learning, memory, and neuronal resilience. Dysregulated mRNA translation control, particularly at the level of initiation, results in reduced global protein synthesis and is a common pathological feature of many neurodegenerative disorders. In mouse models of these diseases, sustained global translational repression drives synaptic dysfunction and loss, ultimately leading to neurodegeneration. Crucially, interventions alleviating this repression restore the proteome, rescue synaptic dysfunction, and promote neuronal survival, leading to their therapeutic potential being assessed in clinical trials. Recently, alternative nodes of regulation have emerged, not only of global mRNA translation-including elongation control-but also of mechanisms fine-tuning subcellular translation in different cellular compartments, notably at synapses and mitochondria. These translation regulatory mechanisms bring a more nuanced understanding of the role of local protein synthesis in neuronal health and disease and the opportunity for novel therapies.