Neurodegeneration Atlas Reveals Disease Subtypes & Potential Biomarkers | News-Medical.net

A newly created proteome atlas of neurodegenerative diseases, published today in the journal Cell, offers an unprecedented level of detail in understanding the molecular underpinnings of conditions like Alzheimer’s and Parkinson’s disease, researchers at St. Jude Children’s Research Hospital announced.

The pan-neurodegeneration atlas (PanNDA) is a comprehensive survey of “proteomes” – the entire set of proteins expressed by cells – across six major neurodegenerative diseases. The atlas incorporates data from over 2,279 individuals, analyzing protein levels, modifications, and interactions to map the complex biological networks disrupted by these illnesses.

“Neurodegenerative diseases form a tangled biological web with overlapping molecular signatures and symptoms,” explained Junmin Peng, PhD, of the St. Jude Departments of Structural Biology and Developmental Neurobiology, and co-corresponding author of the study. “To decode this complexity, we developed PanNDA to provide a wide-ranging, protein-based outlook to better understand the origins of these diseases and to aid in their diagnosis and treatment.”

The research team, a multi-institute collaboration led by St. Jude, found that although some protein changes are common across different neurodegenerative diseases, the most significant alterations are unique to each condition. This suggests that each disease, despite shared characteristics, operates through distinct molecular mechanisms.

Perhaps more surprisingly, the atlas revealed previously unrecognized subtypes within individual diseases. Researchers identified three major subtypes of Alzheimer’s disease, four in Lewy body dementia, and four in frontotemporal degeneration. “These diseases were often thought of as single entities, but using PanNDA, we found significant heterogeneity,” Peng said. “We likewise found over 20 proteins that may serve as biomarkers to separate Alzheimer’s disease into its three subtypes – a significant clinical aid.”

The study also identified key “driver proteins” – those most centrally involved in disease processes – and mapped the intricate networks of protein interactions disrupted by neurodegeneration. Bin Zhang, PhD, of the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, and co-corresponding author, noted that protein network analysis revealed not only the global landscape of protein–protein interactions in each disease, but also local interaction subnetworks and key candidate driver proteins. “Highly predictive protein subnetworks and driver proteins may play causal roles in disease pathogenesis and therefore represent promising targets for therapeutic intervention.”

Researchers were able to correlate previously known aggregated proteins with other changing proteins, providing a more complete picture of disease progression. “We identified all the major aggregated proteins previously known, but with our data, we could correlate these with other proteins that change alongside them,” Peng said. “It’s the first really large-scale, deep analysis of its kind, covering more than 10,000 proteins in the brain.”

The PanNDA resource is now publicly available at https://penglab.shinyapps.io/pannda/, and researchers anticipate it will serve as a valuable tool for the broader neurodegenerative disease research community. The St. Jude Protein Production Facility, equipped to produce proteins in various systems including E. Coli, insect cells, and HEK293 cells, supported the research.

This work builds on a recent investigation, also published in Cell, that combined protein and RNA data to identify drivers of Alzheimer’s disease. The ongoing collaboration aims to refine understanding of each neurodegenerative disease to facilitate the development of diagnostic tools and new treatment strategies. Peng indicated that subtype information, combined with biomarkers, could be used to stratify patients and predict treatment response.