The contribution of ribosome heterogeneity and ribosome-associated proteins to the molecular control of proteomes in health and disease remains unclear. Here, we demonstrate that survival motor neuron (SMN) protein—the loss of which causes the neuromuscular disease spinal muscular atrophy (SMA)—binds to ribosomes and that this interaction is tissue-dependent. SMN-primed ribosomes are preferentially positioned within the first five codons of a set of mRNAs that are enriched for translational enhancer sequences in the 5′ untranslated region (UTR) and rare codons at the beginning of their coding sequence. These SMN-specific mRNAs are associated with neurogenesis, lipid metabolism, ubiquitination, chromatin regulation and translation. Loss of SMN induces ribosome depletion, especially at the beginning of the coding sequence of SMN-specific mRNAs, leading to impairment of proteins that are involved in motor neuron function and stability, including acetylcholinesterase. Thus, SMN plays a crucial role in the regulation of ribosome fluxes along mRNAs encoding proteins that are relevant to SMA pathogenesis.

核糖体异质性和核糖体相关蛋白对健康和疾病中蛋白质组分子控制的贡献仍不清楚。在这里，我们证明运动神经元存活蛋白（SMN）——其丢失会导致神经肌肉疾病脊髓性肌萎缩症（SMA）——与核糖体结合，并且这种相互作用是组织依赖性的。SMN 引发的核糖体优先位于一组 mRNA 的前 5 个密码子内，这些 mRNA 富含 5' 非翻译区 (UTR) 中的翻译增强子序列以及编码序列开头的稀有密码子。这些 SMN 特异性 mRNA 与神经发生、脂质代谢、泛素化、染色质调节和翻译相关。SMN 的缺失会导致核糖体耗竭，尤其是在 SMN 特异性 mRNA 编码序列的开头，导致参与运动神经元功能和稳定性的蛋白质（包括乙酰胆碱酯酶）受损。因此，SMN 在沿着 mRNA 编码与 SMA 发病机制相关的蛋白质的核糖体通量调节中发挥着至关重要的作用。