Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) patients is caused by several factors, including inflammation and oxidative stress.
Uncovering the multiple pathways leading to ALS may suggest new ways to intervene therapeutically. University of Pittsburgh researchers found the Receptor for Advanced Glycation End Products (RAGE) and its ligands, or attached molecules, are increased in the spinal cords of ALS patients, making that area a new potential therapeutic target.
The study, “Receptor for Advanced Glycation End Products and its Inflammatory Ligands are Upregulated in Amyotrophic Lateral Sclerosis,” was published in the journal Frontiers in Cellular Neuroscience.
Therapeutic intervention against ALS requires the targeting of multiple pathways to prevent loss of motor neuronal function. RAGE is present in the central nervous system (CNS) and can be detrimental if triggered by its ligands such as AGEs (advanced glycation end products), S100/calgranulin family members, and High Mobility Group Box-1(HMGB1) proteins.
Pharmacological targeting of RAGE has been known to reduce the rate of neurodegeneration in animal models of Alzheimer’s and Parkinson’s disease. Researchers examined the presence of RAGE in the spinal cord tissue of ALS patients compared to non-ALS controls. The team obtained spinal cord tissue of ALS patients admitted to the Columbia University Medical Center for diagnosis and treatment, and from deceased control subjects with no neurodegenerative disease diagnosis.
Researchers analyzed the tissue, protein, and RNA levels using Western blotting and quantitative real-time PCR (polymerase chain reaction), a genetic technique that analyzes any short sequence of DNA or RNA.
ALS spinal cord tissue displayed increased expression of RAGE and RAGE ligands S100B, CML and HMGB1. The team hypothesized that during pathological processes in ALS, the activation of RAGE in neurons and inflammatory cells, also known as microglia, contributes to the release of reactive oxygen species (ROS) and inflammatory cytokines. These events may induce misfolded protein accumulation, impaired mitochondrial function and growing energy deficits, ultimately causing motor neuron loss.
More experimental work will be needed to confirm this hypothesis, researchers said. “Whether RAGE and its ligands are the cause or the modifier of neurodegenerative disease has yet to be elucidated,” they said in a news release. “However, the upregulation of these molecules may indicate a mechanism, a biomarker, or both. Our findings link upregulation of RAGE and its ligands in ALS-affected tissue, indicating that these molecules are worthy of further investigation.”