REGULATION OF PRE-MRNA PROCESSING IN AMYOTROPHIC LATERAL SCLEROSIS (ALS) AND IN MUSCLE CELLS DIFFERENTIATION

Amyotrophic lateral sclerosis (ALS) is an adult-onset chronic neuromuscular disorder that is characterized by muscle wasting, weakness, and spasticity. ALS is uniformly fatal due to respiratory impairment. This disease is a relatively frequent, 1:100'000, and is present worldwide; 95% of all cases are sporadic, with the remaining 5% of cases showing inheritance. A small percentage of the cases are due to the inactivation of a gene involved in the detoxification of the cell from the damage caused by oxygen free radicals. These mutations represent only about 1% of all ALS patients, so that the cause of the majority of the ALS cases is still unknown. Recently, a novel candidate gene was found that codes for a protein involved in the transport of glutamate. This molecule is normally used to transmit signals to neurons. At high concentrations, however, glutamate is toxic for the cell. The level of this glutamate transporter protein, termed EAAT2, is strongly reduced in tissue from ALS patients. The low protein expression is due to a defect in the maturation of the molecule, which transfers the genetic information from DNA into proteins, called messenger RNA (mRNA). Apparently, the production of abnormal EAAT2 mRNAs is caused by the malfunction of the machinery that performs the maturation step. We propose to investigate the molecular mechanism of this aberrant event in the hope to find the factor(s) that is responsible for the malfunction of the maturation apparatus. This may provide in the long term new targets for diagnosis and the therapy of ALS. In addition we will study the maturation of the mRNA that encodes tropomyosin a key protein in muscle cell function. The study of this model system will improve our understanding of how mRNA maturation factors function during normal cell differentiation and how their function might be altered in disease.