Using more than 600 postmortem frontal cortex samples, researchers built a brain microprotein atlas and found 1,067 high-confidence microproteins missing from reviewed UniProt entries, with several altered in Alzheimer's disease.
At the MKKS locus, a 63-amino-acid microprotein emerged as the dominant translation product—while the canonical 570-amino-acid protein was largely undetected—and its levels were significantly lower in symptomatic Alzheimer's brains.
CRISPR knockout of that microprotein in human microglial cells reduced basal oxygen consumption, ATP-linked respiration and maximal respiration, tying its loss to impaired mitochondrial oxidative phosphorylation.
Across the dataset, many small-ORF products were regulated independently of their parent genes, suggesting standard gene-level analyses may miss Alzheimer's-linked protein changes and new biomarker candidates.