Researchers map over 1,000 unknown microproteins in Alzheimer's brains

Scientists have created the first comprehensive atlas of microproteins in the human frontal cortex, analysing over 600 postmortem samples. They identified 1,067 microproteins absent from standard protein databases, several of which are linked to Alzheimer's disease. The findings expand the known brain proteome and may reveal new targets for neurodegeneration research.

Bottom line — The atlas identifies 1,067 previously unknown microproteins, including one tied to microglial energy metabolism in Alzheimer's.

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• The study, published in Nature Aging, integrated transcriptomics, mass spectrometry and deep-learning-predicted spectra across more than 600 frontal cortex samples from donors with and without Alzheimer's disease.
• A 63-amino-acid microprotein encoded by the MKKS gene was found to be the predominant translation product at that locus and is downregulated in Alzheimer's, per the researchers.
• Loss of this MKKS microprotein impairs mitochondrial respiration in microglia, the brain's immune cells, suggesting a role in bioenergetics.
• Some microproteins are differentially expressed in Alzheimer's independently of the annotated main open reading frame at the same genetic locus, the study reports.
• All 1,067 microproteins were absent from reviewed UniProtKB entries, meaning they were previously unannotated in the standard human proteome.

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