WVU researchers explore new methods to help cells fight against harmful proteins linked to neurodegenerative disorders

Researchers at the West Virginia University School of Medicine are utilizing innovative genetic techniques to explore new methods of helping cells fight against devastating neurodegenerative disorders like Alzheimer’s and Parkinson’s Disease.

The research project was led by David Salcedo-Tacuma, a fifth-year student in WVU’s Department of Biochemistry and Molecular Medicine Graduate Program. Salcedo-Tacuma trains in the lab of David M. Smith, Ph.D., professor for the Department of Biochemistry and Molecular Medicine.

“In order to stay healthy, cells in the body rely on a sophisticated waste management system, powered by proteasomes, which break down and dispose of old and damaged proteins,” he explained. “In diseases like Alzheimer’s and Parkinson’s, this garbage system gets overwhelmed and toxic proteins known as IDPs pile up, causing neurodegeneration. Our research aimed to explore methods of modifying these proteasomes to help cells dispose of these toxic proteins faster and more efficiently.”

Using a gene editing tool called CRISPR, Salcedo-Tacuma and his team focused on altering the proteasome that plays a key role in the protein management process. The proteasome, which contains gates at each end that are normally closed, was modified to remain permanently open, causing it to enter a state of hyperactivity.

Salcedo-Tacuma explained that this opened proteasome caused the cell to enter a state of high-speed protein turnover, where it nearly doubled its rate of protein synthesis, while simultaneously and rapidly breaking down and disposing of old, damaged proteins.

“This open-gate proteasome is not just faster; it’s also surprisingly selective, showing a clear preference for identifying and disposing of the faulty proteins that contribute to life-altering neurodegenerative disorders,” he said.

Researchers found that laboratory models with the altered open-gate proteasomes contained 50% lower levels of the proteins that often contribute to neurodegeneration. When tested on the toxic protein linked to Parkinson’s Disease, known as α-synuclein, researchers observed that models with the hyperactive proteasomes destroyed the harmful protein at five times its normal rate. The hyperactive proteasomes were also observed to more quickly and efficiently destroy the harmful protein known to cause alpha antitrypsin deficiency in liver and lung patients.

These findings were recently accepted for publication in the October, 10, 2025 issue of Science Advances. Salcedo-Tacuma said he is honored to receive publication and share his findings with the medical community, but that he is also eager to continue this important research.

“Receiving publication for this study is a significant milestone for us, as it signifies all of the hard work put into this project over the last several years. We are grateful for this recognition, but we also know our work is far from over. We will continue to test the open-gate proteasome in more advanced laboratory and disease models, as we work towards fighting the battle against devastating neurodegenerative disorders,” he said.

The experiments were designed and conducted by Salcedo-Tacuma, who also ran the imaging, analyzed the data and authored the manuscript. The project was also supported by Dr. Smith; Qamrul Islam, a third-year graduate student in Smith’s lab; Nadeem Asad, a research associate in Smith’s lab; and Raymond Anderson, Ph.D., a biomedical scientist and former student in WVU’s Department of Neuroscience Graduate Program.

“This project was the definition of a team effort, and we would not have been able to have the success we’ve had without the hard work and dedication of everyone involved,” Salcedo-Tacuma said. “Dr. Smith’s expertise and guidance on proteasome biology were foundational and key to our success.”

To learn more about the groundbreaking research conducted at the WVU School of Medicine, visit medicine.wvu.edu/research.