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Alternative splicing generates protein isoforms that are conditionally or differentially expressed in specific tissues. The discovery of factors that control alternative splicing might clarify the molecular basis of biological and pathological processes. We found that IL1-α-dependent up-regulation of 38A, a small ribonucleic acid (RNA) polymerase III-transcribed RNA, drives the synthesis of an alternatively spliced form of the potassium channel-interacting protein (KCNIP4). The alternative KCNIP4 isoform cannot interact with the γ-secretase complex, resulting in modification of γ-secretase activity, amyloid precursor protein processing, and increased secretion of β-amyloid enriched in the more toxic Aβ x-42 species. Notably, synthesis of the variant KCNIP4 isoform is also detrimental to brain physiology, as it results in the concomitant blockade of the fast kinetics of potassium channels. This alternative splicing shift is observed at high frequency in tissue samples from Alzheimer's disease patients, suggesting that RNA polymerase III cogenes may be upstream determinants of alternative splicing that significantly contribute to homeostasis and pathogenesis in the brain.

The role of RNA polymerase (Pol) III in eukaryotic transcription is commonly thought of as being restricted to a small set of highly expressed, housekeeping non-protein-coding (nc)RNA genes. Recent studies, however, have remarkably expanded the set of known Pol III-synthesized ncRNAs, suggesting that gene-specific Pol III regulation is more common than previously appreciated. Newly identified Pol III transcripts include small nucleolar RNAs, microRNAs, short interspersed nuclear element-encoded or tRNA-derived RNAs and novel classes of ncRNA that can display significant sequence complementarity to protein-coding genes and might thus regulate their expression. The extent of the Pol III transcriptome, the complexity of its regulation and its influence on cell physiology, development and disease are emerging as new areas for future research.