ABERRANT RNA PROCESSING IN A NEURODEGENERATIVE DISEASE - THE CAUSE FOR ABSENT EAAT2 A GLUTAMATE TRANSPORTER, IN AMYOTROPHIC-LATERAL-SCLEROSIS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease tha t is characterized by selective upper and lower motor neuron degenerat ion, the pathogenesis of which is unknown. About 60%-70% of sporadic A LS patients have a 30%-95% loss of the astroglial glutamate transporte r EAAT2 (excitatory amino acid transporter 2) protein in motor cortex and spinal cord. Loss of EAAT2 leads to increased extracellular glutam ate and excitotoxic neuronal degeneration. Multiple abnormal EAAT2 mRN As, including intron-retention and exon-skipping, have now been identi fied from the affected areas of ALS patients. The aberrant mRNAs were highly abundant and were found only in neuropathologically affected ar eas of ALS patients but not in other brain regions. They were found in 65% of sporadic ALS patients but were not found in nonneurologic dise ase or other disease controls. They were also detectable in the cerebr ospinal fluid (CSF) of living ALS patients, early in the disease. In v itro expression studies suggest that proteins translated from these ab errant mRNAs may undergo rapid degradation and/or produce a dominant n egative effect on normal EAAT2 resulting in loss of protein and activi ty. These findings suggest that the loss of EAAT2 in ALS is due to abe rrant mRNA and that these aberrant mRNAs could result from RNA process ing errors. Aberrant RNA processing could be important in the pathophy siology of neurodegenerative disease and in excitotoxicity. The presen ce of these mRNA species in ALS CSF may have diagnostic utility.