LSI faculty member aims to uncover a new view of neurodegeneration with Klatskin-Sutker Discovery Fund Award
Life Sciences Institute faculty member Shyamal Mosalaganti, Ph.D., is developing a novel approach to investigate neurodegeneration from a structural perspective with a new award from the LSI’s Klatskin-Sutker Discovery Fund.
A fundamental characteristic of many frontotemporal dementias, including Alzheimer’s disease, is the aggregation of proteins that are normally cleared from the cell in healthy conditions. When operating correctly, these proteins are essential to the neurons’ functions. But when they begin to aggregate, they cause cell damage and ultimately result in neuronal death.
The molecular structures of these protein aggregates offer essential clues about how best to target them, either to break down the aggregates or even prevent aggregation. To date, however, most structural insights have been gleaned from protein fragments that have been either purified outside of the cell or extracted from post-mortem brain tissue.
“When we look at the protein extracted or purified outside the cell, we lose a lot of important contextual information,” explains Mosalaganti, who is a research assistant professor at the LSI and an assistant professor of cell and developmental biology at the U-M Medical School. “With this new funding, we aim to build a platform to study how these protein aggregates form and damage the cell — looking not at artificial states, but peering directly into the neurons.”
Shyamal Mosalaganti’s research may hold the key to unraveling the mysteries of neuronal decay and unlock transformative solutions for combating neurodegenerative diseases.
For this work, Mosalaganti will use an advanced multi-modal microscopy workflow called cryogenic-correlative light and electron microscopy (cryo-CLEM) to visualize the protein aggregates directly in patient-derived neurons. The cryo-CLEM method allows scientists to precisely identify their desired protein complex within a cell using fluorescence microscopy and then reveal the architecture in high-resolution, while the molecule remains in its natural setting.
With this approach, Mosalaganti hopes to uncover new insights into not only the structure of the protein aggregates but also how they might be interacting with their environment and contributing to cell death.
The data from this single-cell work will lay the groundwork for Mosalaganti to broaden the project into brain organoids and diseased tissue.
“Most of the larger funding agencies say they want to fund high-risk, high-reward projects, but they still want to see some initial data first,” says Mosalaganti, who is also an assistant professor of biophysics in the College of Literature, Arts, and Science. “The Klatskin-Sutker funding will allow us to do the critical experiments demonstrating we can solve these structures in their native cellular environment.”
This annual award, established through a generous gift from the Klatskin and Sutker families, provides funding to propel innovative early-stage projects with the potential for a high impact on human health.
"True breakthroughs in understanding neurodegeneration require a novel approach," says Burton Sutker, M.D., who also serves on the LSI Leadership Council. “Shyamal Mosalaganti’s research may hold the key to unraveling the mysteries of neuronal decay and unlock transformative solutions for combating neurodegenerative diseases."
"We are honored to support this research, as this approach may pave the way for groundbreaking discoveries and offer hope for a brighter future for all affected by these devastating conditions," adds Deborah Klatskin.