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The molecular mechanism of loss of glial glutamate transporter EAAT2 in neurodegenerative disease
- Publication Year :
- 2007
-
Abstract
- The glial glutamate transporter EAAT2 is the main mediator of glutamate clearance. Reduced EAAT2 function could lead to accumulation of extracellular glutamate resulting in a form of cell death known as excitotoxicity. In amyotrophic lateral sclerosis (ALS) and Alzheimerfs disease (AD), EAAT2 protein levels are significantly decreased in affected areas. EAAT2 mRNA levels, however, remain constant indicating that alterations in EAAT2 expression are due to disturbances at the post-transcriptional level. What cause the selective loss of EAAT2 in ALS and AD? It was reported previously that the increased expression of EAAT2 splice variants, intron 7-retention and exon 9-skipping, is correlated with the loss of EAAT2 protein in the affected area of ALS patients. Therefore, I generated transgenic mice expressing these two splice variants and found that the transgenic mice exhibited an increase in normal EAAT2 protein level and in the glutamate transport activity compared to the non-transgenic littermates. Could the loss of EAAT2 in disease condition be due to the dysregulation of EAAT2 translation? Some of EAAT2 transcripts contained 5Œ untranslated regions (5ŒUTRs) longer than 300 nucleotides (nts). I found that some factors including corticosterone can regulate the translation of EAAT2 in a primary astrocyte line that constantly expressed an EAAT2 transcript containing the 565-nt 5Œ UTR, primary dissociated culture and mice. The third mechanism of the loss of EAAT2 that I investigated is the upregulation of CYP46A1, cholesterol 24S-hydroxylase in AD patients. I found that the percentage of EAAT2 associated with lipid rafts microdomains is decreased more than half in AD patients when compared to normal controls. Increased expression of CYP46A1 in primary astrocyte line which stably expresses EAAT2 or primary cortical culture could results in the loss of EAAT2 protein and dissociation of EAAT2 from lipid rafts. In summary, disregulation of translation and defects in the association with lipid rafts microdomains, but not splice variants, contribute to the loss of EAAT2 protein in some neurodegenerative diseases including ALS and AD. Therapies developed to enhance the translation of EAAT2 or/and prevent the dissociation of EAAT2 from lipid rafts could be beneficial for the diseases.
Details
- Language :
- English
- Database :
- OpenDissertations
- Publication Type :
- Dissertation/ Thesis
- Accession number :
- ddu.oai.etd.ohiolink.edu.osu1187038549