Atlas of brain microproteins links tiny MKKS peptide to microglial energy in Alzheimer's

Researchers built a frontal cortex microprotein atlas by integrating transcriptomics, mass spectrometry, and deep-learning predicted spectra across 600+ postmortem brains with and without Alzheimer’s disease, identifying 1,067 MPs not present in UniProt and showing that several are differentially expressed in AD. A key finding is the MKKS-derived 63–aa micropeptide micro-MKKS63, which is the predominant translation product, downregulated in AD, and whose loss impairs microglial mitochondrial respiration, implicating MPs in microglial bioenergetics. The atlas expands the brain proteome, reveals decoupling of smORF/MORF expression at some loci, and provides an open-access resource (spectra, sequences, and a browsable app) for studying MPs in aging and neurodegeneration.