Brain microprotein atlas maps molecules linked to Alzheimer’s disease

Researchers have mapped more than 4,300 brain microproteins using human post-mortem tissue samples, uncovering dozens of altered molecules in Alzheimer’s disease. Published in Nature Aging on September 14, the comprehensive database could unlock new mechanisms of human ageing and neurodegeneration.

Unlocking the Dark Matter of the Human Genome

Scientists have uncovered more than 1,000 previously overlooked microproteins in human brain tissue samples, giving researchers the most comprehensive database yet to study these hidden molecules. According to the study published in Nature Aging, dozens of these tiny proteins showed altered expression in people with Alzheimer’s disease. This discovery could pave the way to understanding new mechanisms of ageing and neurodegeneration.

Microproteins are small proteins containing fewer than 150 amino acids. Because of their short length, standard gene and protein sequencing techniques notoriously fail to detect them. In a study published in Nature Aging on September 14, researchers combined multiple methods to pinpoint these molecules in post-mortem samples of the dorsolateral prefrontal cortex—a brain region responsible for cognitive control—from individuals with and without Alzheimer’s disease.

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We might be actually missing a whole layer of biology by overlooking these microproteins.

Bahareh Ajami, neuroimmunologist at Cedars-Sinai Medical Center in Los Angeles, California

Overcoming Detection Barriers With Ribosomal Profiling

Often referred to as the dark matter of the genome, microproteins evade standard detection methods like mass spectrometry because of their compact size. Furthermore, while some microproteins originate from parts of the genome previously considered non-coding, others are produced by coding genes that also manufacture large, known proteins. This dual origin complicates identification using conventional RNA-sequencing techniques.

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To bypass these technical hurdles, study co-author Brendan Miller and his colleagues at the Salk Institute for Biological Studies deployed a combination of mass spectrometry, RNA sequencing, and ribosomal profiling. This final technique gathers all cellular ribosomes—the machines that build proteins from RNA—and sequences the specific strands of messenger RNA bound to them.

Using this multi-method approach, the team analyzed 608 post-mortem brain samples taken from individuals with and without Alzheimer’s disease. Through this work, they identified 4,321 microproteins. Out of that total, 3,217 had never been previously characterized in a standard catalogue of human proteins known as UniProtKB/Swiss-Prot.

Brendan Miller, a neuroscientist at the Salk Institute for Biological Studies in San Diego, California, stated that Alzheimer’s disease is a proteinopathy [wherein] the pathology is in part due to the proteins that have misfolded or accumulated and evoked a toxic response. He added that it should be somewhat urgent to understand the full proteome, including microproteins.

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Deep-Learning Models and Public Data Availability

To parse the massive collection, researchers applied a deep-learning model to 3,001 of the newly identified microproteins. The model ranked them based on its confidence that mass-spectrometry data correctly identified them, assigning a strong level of confidence to 1,067 microproteins.

Although the atlas does not explicitly establish the biological function of these newly catalogued proteins, the research team has made the complete data set publicly available. According to Miller, different laboratories can now download the sequences and design experiments to validate them.