Mouse Protein Atlas: A Key to Understanding Human Health

Cataloging every protein in every tissue of the laboratory mouse gives researchers a reference map they can hold up against human biology, organ by organ and disease by disease. Several large-scale efforts, often grouped under the umbrella term “Mouse Protein Atlas,” have now profiled tens of thousands of proteins across dozens of mouse tissues, creating datasets that serve as both a baseline for healthy biology and a launchpad for understanding what goes wrong in conditions from Alzheimer’s disease to cancer. Because mice share a large fraction of their protein-coding genes with humans but can be studied in ways that human subjects cannot, these atlases fill a gap that no amount of clinical research alone could close.

What the Atlases Actually Map

There is no single, monolithic “Mouse Protein Atlas.” Instead, several overlapping projects have taken increasingly comprehensive snapshots of the mouse proteome, each improving on the last in tissue coverage and detection depth. An early landmark effort used mass spectrometry to characterize nine mouse tissues and identified just over 12,000 proteins, including about 6,300 phosphoproteins carrying nearly 36,000 phosphorylation sites.¹ That was a major advance at the time, but newer datasets have gone much further. A quantitative draft of the mouse proteome and phosphoproteome, published in Nature Methods, expanded the coverage to 41 healthy tissues.² A parallel effort using data-independent acquisition mass spectrometry profiled those same 41 organs in four male mice and quantified over 9,300 proteins against a curated reference database, with more than 6,000 proteins reliably measured in most organs.³

These aren’t just lists. The data tell you which proteins are present in a given tissue, how abundant they are relative to one another, and increasingly, how they are chemically modified and how quickly they turn over. The scope keeps broadening: a 2024 study tracked ten mouse organs across three developmental stages, from one week after birth to eight weeks, and detected over 11,500 protein groups across those organs.⁴ Each new dataset adds resolution, like upgrading from a paper road map to satellite imagery.

Why Mouse Proteins Are a Useful Stand-In for Human Ones

Mice and humans diverged roughly 80 million years ago, but many of the core protein machines inside their cells are recognizably similar. In brain tissue, for example, a direct comparison of postsynaptic proteins found that more than 70% of the proteins in the human postsynaptic density were also present in the mouse version. The overall abundance profile was broadly similar between species, though individual protein families showed real quantitative differences: some neurotransmitter receptor subunits and structural proteins were more abundant in mouse tissue, while a cluster of molecules potentially involved in spine plasticity was enriched in humans.⁵

That high overlap is what makes mouse atlases useful for human health research. When scientists find that a particular protein is heavily expressed in the mouse kidney and involved in filtering waste, there is a reasonable chance a similar protein plays a similar role in the human kidney. But the overlap is not perfect, and the places where it breaks down matter. A study comparing gene modules across human and mouse tissues found that while the same essential biological processes are carried out in both species, the specific sets of genes doing the work have sometimes diverged considerably. The functional architecture is more conserved than the roster of individual players.⁶ This means data about a single mouse gene’s function does not always translate directly to its human counterpart, a caveat that researchers have to keep in mind every time they use mouse data to draw conclusions about people.

Organ-Level Portraits

One of the more powerful applications of these atlases is building protein portraits of individual organs. Each tissue has a distinct protein signature that reflects what it does. When researchers profiled 28 mouse tissues using metabolic labeling, the liver stood out for proteins involved in detoxification, energy metabolism, and the cytochrome P450 enzyme family, all consistent with the liver’s known role as the body’s chemical processing plant.⁷ A dedicated liver-and-plasma study went even deeper, identifying over 7,000 proteins in the liver and nearly 4,700 in plasma, including low-abundance signaling molecules like cytokines, chemokines, and receptors that had previously been difficult to detect.⁸ A significant number of liver proteins turned up in plasma as well, spanning complement factors, coagulation proteins, and molecules involved in insulin and growth-factor signaling. That kind of crossover is exactly why a blood draw can sometimes reveal what is happening inside an organ you cannot biopsy easily.

The heart has received similarly detailed treatment. A recent spatial proteomics study of the mouse heart used machine-learning algorithms to assign over 2,000 proteins to 16 different subcellular compartments with high confidence, starting from just 40 milligrams of tissue.⁹ Knowing not just which proteins are present but where inside the cell they sit is critical for understanding diseases like cardiomyopathy, where protein mislocalization is part of the problem.

Protein Turnover and Why It Matters

A static snapshot of which proteins are present in a tissue is useful, but proteins are not permanent fixtures. They are constantly being built, used, and broken down, and the speed of that cycle varies wildly from protein to protein and from organ to organ. A 2025 atlas measured protein half-lives across the heart, liver, spleen, lung, kidney, gut, plasma, and nine distinct brain regions using a labeling approach where mice were fed food containing a heavy isotope of the amino acid lysine over periods of 8 and 32 days.¹⁰ The resulting data revealed how quickly each tissue refreshes its protein stock, and where the slowest-turning-over proteins sit.

This has direct clinical relevance. A protein with a very long half-life is more likely to accumulate damage over time, including chemical modifications and aggregation, which are hallmarks of neurodegenerative diseases. The turnover atlas also covered phosphoproteins, adding a layer of information about how quickly the chemical “on/off switches” on proteins are themselves refreshed. When the early nine-tissue study examined the relationship between protein abundance and phosphorylation, it found that many proteins are regulated by phosphorylation independently of how much protein is being produced. A typical phosphoprotein is widely expressed across tissues but shows variable, often tissue-specific phosphorylation patterns that fine-tune its activity to local needs.¹

Modeling Alzheimer’s Disease and Cancer

Mouse protein atlases become especially valuable when you compare a healthy baseline against a disease model. In Alzheimer’s research, a transgenic mouse expressing human tau protein was used to compare brain cortex proteins at early and late stages of disease. As tau tangles accumulated, specific proteins shifted in abundance. Glutathione S-transferase P1 and carbonic anhydrase II were progressively down-regulated as disease advanced, while secerin-1 and a proton pump subunit spiked early and then fell in later stages.¹¹ That kind of temporal pattern, where a protein is up early and down later, is exactly the sort of detail that could point toward early diagnostic markers or help explain why the disease worsens over time.

More recent Alzheimer’s work has gone beyond just measuring abundance. A study of the 5XFAD mouse model, which carries five mutations linked to the disease, used three independent techniques to assess not just how much protein is present but how stable those proteins are in hippocampus tissue. Across wild-type and transgenic mice at two and eight months of age, each technique flagged roughly 200 to 500 proteins with disease-related changes in stability.¹² A protein can be present in normal amounts yet misfold or become less thermally stable, and those subtle shifts are invisible to standard abundance measurements. Having the healthy atlas baseline makes it possible to spot them.

In cancer research, both xenograft models (where human tumor cells are transplanted into mice) and genetically engineered mouse models have been used to track protein changes tied to tumor initiation, progression, and metastasis.¹³ One study used an aptamer-based assay that simultaneously measures roughly 5,000 proteins to track plasma changes over time in mice carrying transplanted human lung, breast, colon, or ovarian tumors, looking for the earliest protein shifts that might signal a growing tumor.¹⁴ And in a model of metabolic-associated steatotic liver disease, spatial omics revealed that certain glycan structures known to be associated with cancer in humans appeared at very early stages of liver injury, well before tissue damage was visible under a microscope.¹⁵ That finding hints at the possibility of catching liver disease earlier than current methods allow.

From Infancy to Old Age

Aging rewrites the proteome, and mouse atlases are starting to document exactly how. The developmental atlas mentioned earlier tracked protein changes across ten organs as mice grew from one-week-old pups to eight-week-old adults, identifying 115 proteins that changed in all ten organs over that window and revealing that spliceosome proteins play widespread regulatory roles in early organ development.⁴ Sex-based differences also emerged during this period, a reminder that “the mouse proteome” is not one thing but varies by age, sex, and strain.

At the other end of the lifespan, a separate atlas collected proteomic and transcriptomic data from major tissues at 6, 15, 24, and 30 months of age. One of its more striking findings was that post-transcriptional regulation goes haywire especially after 24 months, roughly equivalent to a human in their late sixties or seventies. Proteins involved in the extracellular matrix accumulated in older tissues, while mitochondrial membrane proteins declined across multiple organs.¹⁶ The same group built a publicly accessible Mouse Aging Proteomic Atlas to share the data broadly. A complementary study spanning ten organs and four age stages identified over 14,700 protein groups and combined them with metabolite data, finding that aging-related metabolites like NAD+, inosine, and xanthine shifted significantly across multiple organs.¹⁷ NAD+ decline in particular has attracted enormous interest in the aging field, and seeing it confirmed at the organ-by-organ protein level in mice strengthens the case for exploring NAD+ precursors as interventions.

How the Gut Microbiome Shapes the Mouse Proteome

The protein atlas concept extends beyond the mouse’s own cells. The trillions of microbes living in the gut influence which proteins the host produces, and mouse proteomics has been instrumental in showing how. In experiments using mice colonized with microbial communities of increasing complexity, from simple defined consortia to a complete transplanted human microbiota, the host’s stool proteome mirrored the complexity of its microbial residents. Different colonization states produced distinct host protein signatures.¹⁸

Going a step further, researchers built tissue-specific metabolic models of 28 mouse tissues using proteomics data and then compared conventionally raised mice with germ-free mice that lacked any gut microbes. The comparison revealed that the microbiota reshapes host amino acid metabolism, which in turn affects glutathione metabolism, one of the body’s main antioxidant defense systems.¹⁹ Without the baseline protein maps of healthy tissues, isolating that effect would have been far more difficult.

Drug Safety and Toxicology

Before a new drug reaches human clinical trials, it goes through extensive testing in animals, and the liver and kidneys bear the brunt of toxicity screening because those organs do most of the metabolic heavy lifting. Toxicoproteomics, the study of how toxic exposures alter the protein landscape, relies on having a detailed healthy-tissue reference. When researchers compare the liver proteome of a drug-treated mouse against the atlas baseline, they can spot early protein shifts that signal organ damage before traditional blood tests flag a problem.²⁰ This is not just an academic exercise; drug-induced liver injury is one of the most common reasons drugs fail in late-stage development or get pulled from the market after approval. Having a comprehensive protein map of the healthy mouse liver makes it faster and cheaper to flag candidate drugs that are likely to cause harm.

Where Mouse Data Falls Short

For all its power, the mouse-to-human translation has real blind spots. As the gene-module comparison study showed, the same biological process can be carried out by substantially different sets of genes in the two species.⁶ This creates a trap: a drug that works beautifully in mice by targeting protein X might fail in humans if the equivalent process in human tissue relies more heavily on protein Y. The immune system is a well-known area of divergence, and many promising cancer immunotherapies that cleared mouse models have stumbled in human trials partly because mouse immune responses are organized differently.

There are also practical limitations. Most atlas datasets have been generated from a small number of inbred mouse strains, typically C57BL/6. Inbred strains are genetically uniform, which reduces noise in experiments but also means the atlas does not capture the natural genetic variation you would see in a wild population, let alone in humans. Sex balance has been uneven too: the 41-organ atlas that quantified over 9,300 proteins used only male mice.³ Given that the developmental atlas found sex-based differences in organ proteomes even in young animals, relying on male-only data risks missing half the picture.

Open Databases and the Next Generation of Atlases

Much of the value of these atlases comes from making the data publicly available. The Mouse Aging Proteomic Atlas, for instance, is hosted online so that any researcher can query it. Specialized databases have also emerged for particular compartments within the cell. The MitoP2 database integrates information on mitochondrial proteins from yeast, humans, and mice, enabling researchers to search for evolutionary conservation of mitochondrial function and to predict which genes might underlie mitochondrial diseases.²¹ Cell-type-specific approaches are also gaining ground. A technique using viral labeling allowed researchers to tag proteins within specific brain cell types in living mice and then pull those proteins out for analysis, revealing cell-type-specific pathways that would be invisible in a whole-tissue homogenate.²²

The trend line is clear: atlases are getting deeper, broader, and more dynamic. Early efforts mapped which proteins exist in which tissues. Current work layers on protein modifications, turnover rates, subcellular locations, metabolite data, and microbiome interactions. The next frontier involves single-cell proteomics, where individual cells rather than tissue chunks are profiled, and spatial proteomics, where the position of proteins within a tissue slice is preserved. Both approaches have already been applied in mouse tissues and are likely to redefine how finely grained these reference maps can get within the next few years.

1
PubMed Central. A tissue-specific atlas of mouse protein phosphorylation and expression
2
PubMed Central. Mass spectrometry-based draft of the mouse proteome
3
Molecular & Cellular Proteomics. A Mouse Protein Atlas for Comprehensive Proteome Profiling and Laterality Analysis
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Nature Communications. The mouse multi-organ proteome from infancy to adulthood
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PubMed Central. Comparative Study of Human and Mouse Postsynaptic Proteomes Finds High Compositional Conservation and Abundance Differences for Key Synaptic Proteins
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PubMed Central. Characterization and comparison of the tissue-related modules in human and mouse
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Molecular & Cellular Proteomics. Initial Quantitative Proteomic Map of 28 Mouse Tissues Using the SILAC Mouse
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PubMed. Comprehensive and quantitative proteome profiling of the mouse liver and plasma
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Molecular & Cellular Proteomics. Systematic spatial proteomics of the mouse heart
10
Cell. Tissue-specific proteome and phosphoproteome turnover atlas of the mouse
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PubMed. Proteomic profiling of brain cortex tissues in a Tau transgenic mouse model of Alzheimer’s disease
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PubMed Central. Analysis of Brain Protein Stability Changes in a Mouse Model of Alzheimer’s Disease
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PubMed. Application of proteomics in the study of rodent models of cancer
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Scientific Reports. Plasma proteome of growing tumors
15
PubMed Central. Spatial Omics Reveals that Cancer-Associated Glycan Changes Occur Early in Liver Disease Development in a Western Diet Mouse Model of MASLD
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PubMed Central. An atlas of the aging mouse proteome reveals the features of age-related post-transcriptional dysregulation
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Genome Medicine. Ten mouse organs proteome and metabolome atlas from adult to aging
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PubMed Central. Host-centric proteomics of stool: a novel strategy focused on intestinal responses to the gut microbiota
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PubMed Central. The gut microbiota modulates host amino acid and glutathione metabolism in mice
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PubMed Central. The role of toxicoproteomics in assessing organ specific toxicity
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PubMed Central. MitoP2: the mitochondrial proteome database–now including mouse data
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PubMed Central. Deep single-cell type proteome profiling of mouse brain by nonsurgical AAV-mediated proximity labeling