Advancing the Future of Neurodegenerative and Aging-related Disease Treatment
09-10-2024
New research led by Seema Mattoo, associate professor of biological sciences at Purdue University promises new therapeutic avenues for aging related disorders like neurodegeneration and diabetes. Published in Cell Stress and Chaperones, Mattoo’s team has identified a novel small molecule inhibitor targeting the protein HYPE (Huntingtin yeast-interacting protein E), which plays a critical role in protein folding—a process that, when disrupted, is implicated in numerous diseases.
The Foundation: Protein Folding and Disease
Proteins, essential for virtually all cellular functions, must fold into specific shapes to be functional. Misfolding of proteins can lead to aggregation, a hallmark of many diseases, including diabetes and neurodegenerative diseases such as Parkinson’s and Alzheimer’s. Mattoo’s research focuses on HYPE, a human FIC (filamentation induced by cAMP) protein that ensures proper protein folding, akin to maintaining a house’s foundation. Over time, the foundation can slip, causing structural issues; similarly, protein misfolding increases with age, leading to various diseases.
HYPE's Role in Neurodegeneration
In 2015, Mattoo’s team demonstrated that HYPE is vital for maintaining protein integrity under cellular stress. They hypothesized that diseases characterized by protein misfolding, such as Parkinson’s, would require HYPE for cellular stress responses. Their findings revealed that HYPE chemically modifies proteins through a process called AMPylation, which can mitigate neurotoxic effects in Parkinson’s disease.
Pioneering a Small Molecule Inhibitor
The Mattoo Lab’s latest breakthrough involved screening tens of thousands of chemical compounds to find activators and inhibitors that can manipulate HYPE's enzyme activity. This process, known as drug screening, is comparable to finding the right key for a lock. After years of rigorous testing, her team has identified the first small molecule inhibitor that effectively blocks HYPE.
Seed funding from Purdue Institute for Drug Discovery (PIDD) and a training grant for her student from the Clinical and Translational Sciences Institute (IN-CTSI) enabled Mattoo to venture outside her realm of expertise to pioneer this important study.
“This discovery is significant because it provides the first prototype for a drug targeting HYPE, a protein central to various diseases,” Mattoo explained. “We anticipate that our inhibitor could lead to development of treatments for conditions like motor neuron diseases and diabetes, where HYPE mutations disrupt regulation of protein folding.”
Validating the Findings
The research has already attracted attention from the broader scientific community, corroborating the pivotal role of HYPE in neurodegenerative and metabolic diseases. Two clinical mutations in HYPE linked to motor neuron defects and early onset diabetes were identified recently, underscoring the protein's significance.
Mattoo's work underscores the importance of targeting fundamental cellular processes to develop effective treatments. The identification of a HYPE inhibitor is a promising step toward addressing diseases rooted in protein misfolding and aggregation.
Future Implications
This pioneering work on HYPE inhibitors marks a transformative step in biomedical research. By targeting the fundamental processes underlying protein misfolding, this research holds promise for developing treatments that could alleviate the burden of several protein misfolding and aging related diseases and improve overall cellular health. This avenue of research continues to be a priority of the Mattoo lab, collaborative aspects of which are currently being funded through the Purdue Life Sciences Summit initiative.
About the Department of Biological Sciences at Purdue University
Purdue Biological Sciences is the largest department in the Life Sciences at Purdue University. As part of Purdue One Health, we are dedicated to pioneering scientific discoveries and transformative education at the cutting edge of innovation. From molecules to cells, from tissues to organisms, from populations to ecosystems - we bring together multiple perspectives, integrating across biological scales to advance our understanding of life and tackle the world’s most pressing challenges. Learn more at bio.purdue.edu/.
Writer: Alisha Referda, areferda@purdue.edu
Source: Seema Mattoo, smattoo@purdue.edu