Brain atlas catalogs thousands of overlooked microproteins tied to Alzheimer's
Salk Institute researchers Brendan Miller and Alan Saghatelian led a Nature Aging study that catalogs thousands of brain microproteins—typically fewer than 150 amino acids and long excluded from standard genetic databases because they are hard to detect and often sit in small open reading frames inside or near larger genes. Traditional sequencing therefore tends to credit nearby primary genes and miss the shorter molecules.
To map them in the frontal cortex, a region heavily affected by Alzheimer’s, the team built a custom reference by RNA-sequencing tissue from 12 postmortem human brains and adding those transcripts to the known human protein catalog. They then searched mass spectrometry data from 610 brain samples and found 4,321 microproteins, more than 3,000 of them unreviewed in manually curated databases. Ribosome profiling and the deep-learning tool PROSIT, which scores whether mass-spectrometry fragments look like genuine peptides, narrowed this to 1,067 unreviewed microproteins with high-confidence evidence in the brain.
Dozens of these molecules differed between people without the disease and those with symptomatic Alzheimer’s. A microprotein from BCL3 was less abundant in symptomatic brains; one from RAB3C was more abundant. When those two were introduced into laboratory-grown human microglia, they remained stable and occupied specific intracellular locations. About half of the microproteins were regulated independently of their larger parent genes: microprotein RNA often changed in Alzheimer’s while RNA for the main gene did not, a pattern confirmed in a separate patient cohort. The atlas therefore argues that conventional gene catalogs capture only a fraction of the brain’s functional molecules, including ones tied to cellular energy production and genetic regulation.
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