DEVELOPMENT OF A CONDITIONAL MOUSE MODEL OF FAMILIAL AMYOTROPHIC LATERAL SCLEROSIS (FALS) TO STUDY THE REVERSIBILITY OF MUTANT SOD1-INDUCED NEUROTOXICITY

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by motor neuron loss in the brainstem and spinal cord leading to paralysis and death. About 10% of ALS cases are familial, and among those about a fifth is caused by mutations in the gene coding for Cu/Zn superoxide dismutase (SOD1). Transgenic mice for a mutant form of SOD1 develop a pathology similar to that observed in ALS patients. Despite many hypothesis have been formulated (free radicals overproduction, protein aggregate formation), the mechanism of SOD1 mediated selective motor neuron degeneration and the course of events leading to motor neuron death are not known. Here we propose the development of a new SOD1 transgenic mouse model, where the expression of mutant SOD1 can be temporally controlled. We will use a binary system constituted by a tTA (a bacterial derived transactivator) transgenic mouse strain and a mutant SOD1 transgenic mouse strain. In these transgenic mice, mutant SOD1 is under the control of a promoter that can be activated by tTA binding. By crossing these two strains we will obtain some animals where both transgenes are present. These animals will constitutively express the responsive gene, mutant SOD1, in those areas where also tTA is expressed. Doxycycline, once administered orally, will bind to tTA and block its binding to SOD1 promoter. So we will be able to block mutant SOD1 expression during the development of the pathology, before and after symptoms onset. In this way we will study whether the mutant SOD1-induced motoneuron dysfunction can be halted and/or reversed by removal of the toxic agent. Moreover, we will identify the phases after which the progression pathology cannot be stopped. We will be able to increase the existing knowledge on the mechanisms leading to selective motor neurons death, with the aim of devising therapeutic targets for intervention.