Amyotrophic lateral sclerosis (ALS) induced changes in basigin expression patterns
Office of the Provost, Johns Hopkins University
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor function due to premature spinal and cortical motor neuron degeneration and death. Mutations in the superoxide dismutase 1 (SOD1) gene cause approximately 20% of inherited cases of ALS. Overexpression of a mutant form of SOD1 (G93A) in mice appears to produce disease progression through an unknown gain of toxicity. To further elucidate mechanisms of neurodegeneration in ALS, we examined expression patterns of the transmembrane glycoprotein, basigin (CD147, Emmprin) in end-stage of the SOD1 G93A mouse model. Basigin, a member of the immunoglobulin superfamily, has various physiological roles including trafficking of monocarboxylate transporters (MCTs) to the plasma membrane, induction of matrix metalloproteinases (MMPs), and leukocyte activation. We focused on interactions of basigin with MCTs and implications for energy-metabolism in the disease state. The astrocyte-neuron lactate shuttle hypothesis states that lactate release from glucose metabolism in glia fuels neuronal metabolism, particularly in states of oxidative stress. Previous studies have shown that inhibition or down-regulation of MCTs leads to impaired lactate transport and neuronal degeneration, likely due to a lack of energy resources. Basigin is essential for localization of MCT1 and MCT4 to the plasma membrane, and inhibition of basigin has been shown to prevent lactate release by astrocytes. Additionally, basigin has been implicated in several other neurological diseases, including roles in leukocyte transmigration in multiple sclerosis and regulation of the γ-secretase complex in Alzheimer's disease. Interactions with MCT isoforms and implication in related diseases make basigin a viable candidate for study in ALS. We show that basigin co-localizes with MCT1 at the plasma membrane and is well-expressed in myelin-rich areas. We also show that basigin mRNA levels are reduced in brain and spinal cord in SOD1 end-stage disease. Basigin protein levels show differential expression, but not uniform down-regulation. These preliminary results indicate that basigin is likely involved in ALS- related neurodegeneration. Further investigation of the role of basigin in disease and normal states may provide insights regarding pathological changes in ALS.
Basigin, ALS, Amyotrophic lateral sclerosis