Aging is the greatest known risk factor for neurodegenerative diseases, but scientists are still working to understand how age-related molecular changes trigger conditions such as Huntington’s disease and amyotrophic lateral sclerosis (ALS).
Researchers have identified a protein signaling pathway that may explain how aging contributes to the toxic protein accumulation associated with Huntington’s disease, ALS, and other age-related neurodegenerative disorders.
Investigating the Connection Between Aging and Neurodegeneration
A research team led by Professor Dr. David Vilchez at the CECAD Cluster of Excellence for Aging Research studied this connection using the microscopic nematode worm Caenorhabditis elegans. The scientists examined a cellular signaling pathway that becomes more active with age and may promote the buildup of misfolded proteins.
The study, titled “The aging factor EPS8 induces disease-related protein aggregation through RAC signaling hyperactivation,” was published in Nature Aging.
The researchers focused on EPS8, an aging-related protein, and the signaling pathways it regulates. Earlier studies found that EPS8 accumulates as worms age, activating harmful stress responses that can reduce lifespan.
EPS8 May Promote Toxic Protein Aggregation
The study found that elevated EPS8 levels and increased activity in related signaling pathways can promote abnormal protein aggregation and neurodegeneration. Toxic protein buildup is a key characteristic of several age-associated neurological diseases, including Huntington’s disease and ALS.
When researchers reduced EPS8 activity, toxic protein aggregates formed less frequently. The intervention also helped protect nerve cell function in worm models of both Huntington’s disease and ALS.
“We are delighted to have uncovered a molecular mechanism that may help explain how aging contributes to diseases such as ALS and Huntington’s disease,” says first author Dr. Seda Koyuncu. “For years, we have known that age is the leading shared risk factor for many neurodegenerative diseases. However, the precise way age-related changes contribute to disease remains largely unknown. This study may help fill an important part of that gap.”
Findings Replicated in Human Cell Models
EPS8 and its associated signaling molecules have been conserved throughout evolution and are also present in human cells. This enabled the researchers to test whether the mechanism observed in worms could also be relevant to human neurodegenerative disease.
Lowering EPS8 levels in human cell models of Huntington’s disease and ALS produced results similar to those observed in C. elegans. The intervention reduced the accumulation of toxic protein aggregates in the cells.
“It is incredibly exciting that the mechanisms we identified in C. elegans are also conserved in human cell models,” says Professor Dr. David Vilchez. The findings demonstrate how simpler organisms, such as nematode worms, can help scientists uncover disease mechanisms that may also affect humans.
EPS8 Could Become a Future Therapeutic Target
Researchers do not yet know exactly how increased EPS8 activity causes toxic proteins to aggregate. Nevertheless, the findings help address a major question in neurodegenerative disease research by identifying a possible molecular link between aging and brain degeneration.
The results also suggest that EPS8 and its signaling partners could become potential targets for future treatments. Therapies designed to regulate this pathway may one day help slow the progression of ALS, Huntington’s disease, and other age-related neurodegenerative disorders, although further research is needed.
Source: www.sciencedaily.com