Hope for future cures of several debilitating diseases may be found in the brain of an ordinary mouse.

Every year incurable degenerative diseases like Alzheimer’s, Parkinson’s and multiple sclerosis threaten the lives of millions of Americans, particularly the elderly. Now research being conducted at the Environmental Molecular Sciences Laboratory, a U.S. Department of Energy (DOE) national scientific user facility located at the Pacific Northwest National Laboratory (PNNL) in Richland, Washington, is giving reason for hope. Their research, aimed at accelerating the development of cures for these frightening disorders, is being conducted through—as incredible as it sounds—advanced 3-D mapping of a mouse’s brain.

Richard D. Smith, a Battelle Fellow at PNNL, is spearheading the effort. His proteome mapping, a breakthrough developed in collaboration with Desmond Smith of the University of California-Los Angeles’ (UCLA) David Geffen School of Medicine, is the first to apply quantitative proteomics, the study of protein structures and functions, with three-dimensional imaging. Prior to this, proteomics, which uses a specially modified instrument called a mass spectrometer to identify and match proteins, was akin to flying blind over a lake of proteins.

“Proteins are the lead actors—the most important part of the picture,” said Smith. “They are the molecules that do the work of the cells.”

Smith, who holds 31 patents and has been the recipient of seven R & D 100 awards, has devoted the last decade to developing and applying new methods for probing the entire array of proteins—or proteomes—that are expressed by a cell, tissue or organism. His research is significant to neuroscience since proteomes may be considered the protein counterpart to a genome, and can provide new insights into the brain’s operation.

To produce the protein maps, Smith and his colleagues characterized brain pieces in hundreds of small one-millimeter cubes, or voxels, to determine where proteins appear in the brain and where they vary in abundance. By labeling all proteins from another mouse brain, they developed reference points to compare the amounts of protein in the different parts of the brain from one mouse to another.

“We labeled them to have reference points so that we know we’re looking at the same protein between different parts of the brain and from one mouse to another,” said Smith. “Knowing their location and how their abundance changes in different cases is important for understanding their functions.”

The next step for Smith and his researchers is to develop 3-D visualization of an entire mouse brain, then compare proteome maps for healthy brains with others who have diseases with strong similarities to humans.

The brain’s molecular complexity has challenged neuroscience. Research found that roughly one-third of the mammalian genome, or the complete set of genetic material, appears to be dedicated exclusively to brain function. But with information such as the types and locations of a living organism’s organic molecules, or biomolecules, within the mammalian brain, scientists are beginning to understand the origin and progression of brain diseases. Holding them back, however, have been current imaging techniques that, in spite of good spatial resolution technology, can identify one or only a few proteins (generally the most abundant) at a time. But by using a mouse’s brain, now scientists are able to detect more than a thousand different proteins in a single experiment and map them to the brain structures.

The research represents a major step forward for completely characterizing detailed spatial abundance patterns of the brain proteome and provides a methodological basis for future studies. Contrasts in location and abundance of proteins might signal the earliest detectable stages of Alzheimer’s disease, Parkinson’s disease and other neurological diseases. This research could reveal possible blood biomarkers that would enable better diagnosis or identify new protein targets for the treatment of neurological diseases, raising the hope that such diseases might be curbed if caught and treated early.