Abstract
The etiology of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder characterized by progressive muscle weakness and spasticity, remains largely unknown. Approximately 5–10% of cases are familial, and of those, 15–20% are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Mutations of the SOD1 gene interrupt cellular homeostasis and contribute to cellular toxicity evoked by the presence of altered SOD1, along with other toxic species, such as advanced glycation end products (AGEs). AGEs trigger activation of their chief cell surface receptor, RAGE (receptor for advanced glycation end products), and induce RAGE-dependent cellular stress and inflammation in neurons, thereby affecting their function and leading to apoptosis. Here, we show for the first time that the expression of RAGE is higher in the SOD1 transgenic mouse model of ALS vs. wild-type mouse spinal cord. We tested whether pharmacological blockade of RAGE may delay the onset and progression of disease in this mouse model. Our findings reveal that treatment of SOD1 transgenic mice with soluble RAGE (sRAGE), a natural competitor of RAGE that sequesters RAGE ligands and blocks their interaction with cell surface RAGE, significantly delays the progression of ALS and prolongs life span compared to vehicle treatment. We demonstrate that in sRAGE-treated SOD1 transgenic animals at the final stage of the disease, a significantly higher number of neurons and lower number of astrocytes is detectable in the spinal cord. We conclude that RAGE antagonism may provide a novel therapeutic strategy for ALS intervention.
Highlights
Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease, is a progressive and terminal neurological disorder, which results in severe disability and death within 5 years after diagnosis (Ferraiuolo et al, 2011)
Detailed analysis of the survival and longevity span revealed that male mice injected with soluble RAGE (sRAGE) displayed on average a higher probability of surviving for a longer time after the disease onset; p = 0.007 (Figure 3A), and on average a longer lifespan compared to the murine serum albumin (MSA)-treated group (138.5 ± 3.1 vs. 130.6 ± 3.1, respectively); p = 0.01 (Figure 3B)
The percentage of days lived by sRAGE mice was significantly higher than that of MSA mice (29.34% ± 0.66 vs. 27.67% ± 0.63, respectively (p = 0.02), when compared to non-transgenic SJL mice used as a reference, 100%, 472 days, as published
Summary
Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease, is a progressive and terminal neurological disorder, which results in severe disability and death within 5 years after diagnosis (Ferraiuolo et al, 2011). Mutations of the SOD1 gene lead to the loss of biological function of the SOD1 molecule but they disrupt normal cellular homeostasis and result in accumulation and aggregation of mutated SOD1 as well as other molecular species such as advanced glycation end products (AGEs; Albers and Beal, 2000; Kato et al, 2001). AGEs trigger activation of RAGE (receptor for advanced glycation end products) and along with reactive oxygen species are primary contributors to cellular stress, endoplasmic reticulum stress, accumulation of abnormal protein aggregates, and mitochondrial dysfunction (Daffu et al, 2013). We demonstrated that RAGE and its inflammatory ligands S100B, CML-AGE, and HMGB1, were coexpressed and upregulated in thoracic spinal cord samples of human ALS patients compared to controls (Juranek et al, 2015)
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