Researchers at Penn State have identified a new potential treatment approach for Alzheimer’s and other neurodegenerative diseases. Their discovery that disrupting sugar modifications of specific proteins can promote cell repair and reverse cellular abnormalities seen in these diseases holds the promise of improving the quality of life for Alzheimer’s patients.
Published in iScience, the study focuses on early cellular changes shared by Alzheimer’s, Parkinson’s, and ALS and suggests that targeting these proteins could offer new tools to halt or reverse disease progression. In leading the research, Scott Selleck highlights the need to address these early deficits, distinct from late-stage pathological changes targeted by current treatments.
Roughly 6.9 million Americans aged over 65 have Alzheimer’s disease, but its exact biological cause remains unclear. Heparan sulfate–modified proteins involved in cell signaling are suspected to play a role in Alzheimer’s development.
In their study, Penn State researchers found that these proteins regulate cellular processes linked to various neurodegenerative diseases. Heparan sulfate–modified proteins are found on cell surfaces and in the spaces between cells.
Named for their sugar polymer structure with sulfate groups, heparan sulfate modifies proteins, enabling them to form signaling complexes crucial for cell growth and interaction with their surroundings. These pathways also govern autophagy, a cell repair process that eliminates damaged components.
“In early stages of neurodegenerative diseases, cells have reduced repair capacity due to compromised autophagy,” explained Selleck. Their study found that heparan sulfate-modified proteins hinder autophagy-dependent cell repair. By disrupting these proteins’ sugar modifications, autophagy levels increase, allowing cells to manage damage better.
The researchers discovered that lowering the function of heparan sulfate-modified protein in human and mouse cells also improved mitochondrial function, which is responsible for cell energy production, and reduced lipid buildup inside cells—a common issue in neurodegenerative diseases.
In an Alzheimer’s fruit fly model with presenilin protein deficits, similar to human mutations causing early disease onset, reducing heparan sulfate chain function prevented neuron death and corrected other cell defects. According to the researchers, these findings align directly with recent human genetics research.
Individuals with mutations in the presenilin gene PSEN1 typically develop Alzheimer’s in their mid-40s. However, they also inherit a rare genetic change in the APOE protein. In that case, the disease onset is delayed, sometimes by decades.
APOE plays a role in lipid transport and binds to heparan sulfate. This recent finding reduces APOE binding to heparan sulfate, suggesting a potential treatment avenue by targeting enzymes involved in heparan sulfate production to block neurodegeneration in humans.
The study shows that altering the structure of heparan sulfate modifications can block or reverse early cellular problems in Alzheimer’s models. “We prevent neuron loss, correct mitochondrial issues, and improve behavior deficits, indicators of nervous system function,” Selleck noted. These findings propose a promising target for future treatments to rescue early abnormalities seen in many neurodegenerative diseases.
Additionally, the researchers explored how eliminating heparan sulfate chain production in human cells affected gene expression. They found significant changes in over 50% of genes associated with late-onset Alzheimer’s disease, including APOE. This suggests a link between heparan sulfate-modified proteins and more common forms of Alzheimer’s disease that develop later in life.
“We need to focus on early cellular changes in disease and develop treatments to reverse them,” emphasized Selleck. By altering heparan sulfate-modified proteins, we can block common neurodegenerative disease markers like reduced autophagy, mitochondrial defects, and lipid accumulation. These proteins hold promise as targets for new drugs.
The researchers believe that disrupting this pathway to enhance cell repair systems could benefit many other diseases with autophagy issues. “Manipulating this pathway could have broad applications across various medical conditions,” added Selleck.
Journal reference:
- Nicholas Schultheis,Alyssa Connell et al., Altering heparan sulfate suppresses cell abnormalities and neuron loss in Drosophila presenilin model of Alzheimer Disease. iScience. DOI: 10.1016/j.isci.2024.110256.