Longevity
Salk researchers map 1,000-plus unknown microproteins in Alzheimer's brain tissue
By Life and Health Today Staff, . Life and Health Today.
Researchers at the Salk Institute have published what they describe as the first atlas of microproteins in the human frontal cortex, comparing brain tissue from people who had Alzheimer's disease with tissue from people who did not. The study appeared in the journal Nature Aging.
Microproteins are very small proteins, typically 150 amino acids or fewer in length, produced from short stretches of genetic code called small open reading frames. Because standard protein databases were built on gene models that exclude these short sequences by design, microproteins have been systematically invisible to most research tools.
To build the atlas, the team analyzed existing transcriptomic data (readouts of which genes are active in a tissue) and mass spectrometry data (a technique that identifies proteins by their molecular weight and structure) from postmortem frontal cortex samples drawn from nearly 500 individuals, including samples from the Religious Orders Study and Memory and Aging Project cohort, according to Genetic Engineering News. They used a custom AI-powered tool called ShortStop, developed in the lab of senior author Alan Saghatelian, to find microprotein sequences that standard searches would miss.
The result was 1,067 previously uncharacterized microproteins absent from reviewed entries in UniProtKB, the main curated protein database, the paper reports. Some of these microproteins were expressed at different levels in Alzheimer's disease samples compared with non-Alzheimer's samples, and Alzheimer's disease cells tended overall toward higher microprotein expression, according to the paper.
The finding that drew the most attention in the study involved microglia, the brain's resident immune cells, which are known to change their behavior during aging and neurodegeneration. The researchers identified a 63-amino-acid microprotein encoded at a location in the genome called the MKKS locus. That microprotein appeared to be the predominant protein product at that locus and was downregulated in Alzheimer's disease tissue. When the researchers knocked out the gene encoding it in microglia in the lab, the cells showed impaired mitochondrial respiration, meaning their ability to generate energy was reduced. This suggests the microprotein may play a role in how microglia power themselves, though the work does not establish that the microprotein's absence causes Alzheimer's disease or its symptoms.
Saghatelian, quoted in Genetic Engineering News, noted a broader implication: the most abundant and most tissue-relevant protein at a given genetic location can be one that has never been annotated. He also cautioned that not every microprotein in the atlas should be assumed to be biologically active. Some may be markers of disrupted gene activity rather than functional molecules in their own right.
What this does not show is whether any of these microproteins drive disease, protect against it, or are simply present. The knockout experiment was conducted in microglia in a laboratory setting, not in living people, and the atlas itself is built from postmortem tissue. The connection between the MKKS microprotein and Alzheimer's disease is an association observed in tissue samples, not a demonstrated cause. First author Brendan Miller, a postdoctoral researcher in Saghatelian's lab, described the atlas as a resource other researchers can download and use to investigate microprotein function, which signals that the interpretive work is still ahead.
The open question is whether any of the 1,067 newly identified microproteins can be shown, in controlled experiments, to have a causal role in neurodegeneration. The atlas makes that work possible in a way it was not before. Whether it leads anywhere therapeutically depends on experiments that have not yet been done.