UMD Lab Pioneers Tool for Eavesdropping on Neurons

Researchers at the University of Maryland have developed a technique to profile the proteins inside of a single live nerve cell, a breakthrough in analytical neuroscience that will lead to new understanding of normal brain development and advance diagnostics and therapeutics for diseases such as Alzheimer’s and Parkinson’s.

The technical milestone was achieved with an ultrasensitive, high-resolution mass spectrometer that was built in-house, and is sensitive enough to detect hundreds of different proteins in individually characterized neurons in a live brain section. The innovation was featured recently on the cover of Analytical Chemistry.

“This paper expands the analytical toolbox of neuroscience,” said Peter Nemes, an associate professor in the Department of Chemistry and Biochemistry who led the research. “It lays the groundwork for a proteomic-driven classification of cell types in the brain.”

In bioanalytical chemistry, mass spectrometry provides information about the molecular composition of a sample—what is present and in what quantity—by “weighing” its molecules. The challenge for neuroscience has been to extract and detect the proteins generated by a cell from a very small sample.

Scientists have possessed tools to detect proteins in cells for years, but have lacked the technology to identify and quantify these molecules in all their diversity. The advanced ultrasensitive high-resolution mass spectrometry instrument developed by Nemes’ lab introduces a new capacity to accomplish this. Because the function of any cell, including a neuron, intimately depends upon the proteins it generates, the novel ability of the instrument is vital to greater understanding of the development and function of brain cells.

To meet this challenge, Nemes refined the sensitivity of his mass spectrometer down to the scale of a single neuron: about 15-50 micrometers, or less than the width of an average human hair.

“There are so many exciting applications for Peter’s method to identify the full complement of proteins in physiologically characterized neurons, including for cells grown in culture, in brain slices, and even in the whole brain,” said Elizabeth Quinlan, professor in the Department of Biology, the Clark Leadership Chair in Neuroscience, and director of the Brain and Behavior Institute.

Nemes’ development of ultrasensitive high-resolution mass spectrometry for individual neurons is poised to elucidate the molecular basis for functional differences between neurons. Such increased understanding to could lead to new approaches for diagnosing and treating neurological diseases that affect 50 million or more people in the United States each year.

“Once we can characterize the proteome of a neuron, we can think outside of the proverbial box,” said Nemes. “How many other important proteins have we overlooked due to a lack of technological capability? Are we missing any key culprits of neurodegenerative diseases, such as other dysregulated proteins, simply because they do not fit into the canonical understanding of the brain?”

He envisions the continued development of such cutting-edge technologies and is keen to identify their broad applications through further collaborations at UMD.

“What’s exciting for us in College Park are the numerous colleagues working in different facets of neuroscience and developmental neurobiology who think strategically about integrating complementary expertise to pursue big problems in neuroscience with grand technologies,” said Nemes. “These teams can blossom really quickly, and they can have a major impact as they tackle pressing challenges in science and society with fresh—and even transformative—insights.”