Alternative splicing generates a Ribosomal Protein S24 isoform induced by neuroinflammation and neurodegeneration

Neuroinflammation, particularly that involving reactive microglia, the brain’s resident immune cells, is implicated in the pathogenesis of major neurodegenerative diseases. However, early markers of this process are in high demand. Multiple studies have reported changes in ribosomal protein (RP) expression during neurodegeneration, but the significance of these changes remains unclear. Ribosomes are evolutionarily conserved protein synthesizing machines, and although commonly viewed as invariant, accumulating evidence suggest functional ribosome specialization through variation in their protein composition. By analyzing cell type-specific translating mRNAs from mouse brains, we identify distinct RP expression patterns between neurons, astrocytes, and microglia, including neuron-specific RPs,Rpl13aandRps10. We also observed complex expression relationships between RP paralogs and their canonical counterparts, suggesting regulated mechanisms for generating heterogeneous ribosomes. Analysis across brain regions revealed thatRplp0andRpl13a, commonly used normalization references, show heterogeneous expression, raising important methodological considerations for gene expression studies. Importantly, we show thatRps24, an essential ribosome component that undergoes alternative splicing to produce protein variants with different C-termini, exhibits striking cell type-specific isoform expression in brain. TheRps24cisoform is predominantly expressed in microglia and is increased by neuroinflammation caused by aging, neurodegeneration, or inflammatory chemicals. We verify increased expression of S24-PKE, the protein variant encoded byRps24c, in brains with Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, and relevant mouse models, using isoform-specific antibodies. These findings establish heterogeneous RP expression as a feature of brain cell types and identifyRps24c/S24-PKE as a novel marker for neuroinflammation and neurodegeneration.