Nature Aging publishes a protein atlas from 610 postmortem frontal cortex samples: a 63-amino-acid protein was the most frequently detected product of MKKS

Nature Aging publishes a protein atlas from 610 postmortem frontal cortex samples: a 63-amino-acid protein was the most frequently detected product of MKKS

On September 14, Nature Aging published a study of short proteins in 610 postmortem frontal cortex samples. A single gene can produce several proteins, and their relative proportions vary across tissues.

Short proteins are difficult to detect because digestion leaves few measurable fragments. The authors used long RNA sequences from the same brain region to compile a catalog of possible short proteins, then searched for their fragments using mass spectrometry, a method that measures molecular mass. Separately, ribosome profiling identified the regions of RNA that cells read to make proteins.

Across the 610 samples, 4 321 short proteins met the identification threshold. Of these, 3 217 were absent from the manually reviewed section of UniProt; for 1 067, the measured fragments closely matched the predicted spectrum.

Protein reference databases list a 570-amino-acid protein for the gene MKKS. In the frontal cortex, its most frequently detected product was micro-MKKS63, a 63-amino-acid protein: mass spectrometry yielded more than a thousand fragment matches for it. Ribosome profiling confirmed that cells read the RNA region encoding micro-MKKS63.

Levels of micro-MKKS63 were lower in postmortem cortex from people with symptomatic Alzheimer’s disease. The authors investigated its role in HMC3, a human microglial cell line. Microglia are the brain’s immune cells. In these cells, micro-MKKS63 was found near mitochondria, where cells produce energy.

The authors then used CRISPR, a DNA editing method, to disable the region encoding micro-MKKS63 in two independent cell lines. Both lines showed decreases in basal and maximal oxygen consumption and in respiration linked to energy production. Studying genes like this in the brain requires measuring their short proteins separately: these may be the main products detected in a tissue and may alter cell function.