We and other investigators have recently demonstrated that transcript mutation could be an important factor in the pathophysiology of age-related neurological disorders. The increase in the number of abnormal messenger RNA, with the consequent synthesis of altered proteins, can lead to abnormal metabolic function and cell death. Our recent findings of the presence of multiple aberrant glutamate transporter EAAT2 (excitatory amino acid transporter 2) transcripts, including intron-retention and exon-skipping, in sporadic amyotrophic lateral sclerosis (ALS) as well as in Alzheimer's disease (AD) are good examples. EAAT2 is an astroglial glutamate transporter and is the predominant glutamate transporter. About 60-70 percent of sporadic ALS patients have a 30-95 percent loss of EAAT2 protein in motor cortex and spinal cord. The aberrant EAAT2 transcripts were highly abundant presented in neuropathologically affected areas of ALS patients. The aberrant EAAT2 transcripts, possibly as a consequence of abnormal splicing, can lead to loss of glutamate transporters, with subsequent increase of extracellular glutamate concentration and excitotoxic neurodegeneration. Are there other genes also affected? In this pilot study, we propose to develop a method based on the representational difference analysis (RDA) to identify aberrant transcripts in age-related neurological disorder brains.
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