New brain atlas reveals thousands of overlooked microproteins linked to Alzheimer’s disease

Scientists have mapped thousands of previously unidentified proteins in the human brain, many of which are altered in Alzheimer's disease. Published in Nature Aging, the study provides a detailed catalog linking these short proteins to brain cell energy production and genetic regulation. These findings suggest that traditional genetic databases only capture a fraction of the brain's functional molecules.

Microproteins, which are very short proteins containing fewer than 150 amino acids, are challenging to detect due to their length. They originate from small open reading frames within larger genes, often located near them. Researchers at the Salk Institute for Biological Studies led by Brendan Miller and Alan Saghatelian aimed to create an atlas of microproteins in the frontal cortex, a brain region affected by Alzheimer's disease.

They constructed a custom genetic database using advanced RNA sequencing on tissue from 12 postmortem human brains. This database was then added to the standard reference database of known human proteins. By analyzing mass spectrometry data from 610 brain samples, the team discovered 4,321 microproteins, with over 3,000 considered unreviewed.

To verify these unreviewed microproteins, the researchers used ribosome profiling and a deep learning tool called PROSIT. The analysis identified 1,067 unreviewed microproteins with strong evidence of existing in the brain. The team then investigated whether these microproteins change in Alzheimer's disease by comparing mass spectrometry data from individuals with and without the disease.

They found dozens of microproteins with altered levels in symptomatic individuals. For example, a microprotein derived from the BCL3 gene was less abundant in symptomatic individuals, while a microprotein from the RAB3C gene was more abundant. The researchers also discovered that many microproteins are regulated independently of their larger parent genes, a phenomenon confirmed in a separate dataset.

One notable microprotein is encoded by the MKKS gene, which is typically associated with a rare developmental disorder. However, the team found that the dominant product of the MKKS gene in the frontal cortex is the small microprotein rather than the large primary protein. This microprotein was found to be lower in the brains of individuals with symptomatic Alzheimer's disease.

The researchers also identified a connection between this microprotein and mitochondrial function, suggesting a potential link to Alzheimer's disease.