Mechanisms of Neuronal Death in a Transgenic Mouse Model for Amyotrophic Lateral Sclerosis

Neurons are large post-mitotic cells with a high metabolic activity and a highly complex morphology characterized by a dendritic tree that consists of a network of processes, and an axon that can have length of up to 104 times the diameter of the cell body. Because of this complexity the maintenance of the functional and structural integrity of neurons throughout life is a complex task that requires sophisticated transport, damage control and repair machineries. Hence, it is not surprising that aging is associated with structural and functional deterioration of the central nervous system and that neurodegenerative diseases (diseases that cause the premature loss of neurons) are among the dominant disorders associated with aging. The knowledge on processes involved in normal aging and neuronal death in neurodegerative diseases is increasing, but far from complete. Intervention in these processes is therefore not yet possible. Amyotrophic lateral sclerosis (ALS) is a fatal disease in which motoneurons in the spinal cord, brain stem and motor cortex degenerate. This disease has an incidence of 2-3 per 100.000 people, meaning that 300-450 people are diagnosed with the disease each year. The survival of ALS-patients is on average 3 years after diagnosis. The first symptoms are usually fatigue, muscle cramps, and weakness in the muscles of one of the limbs, progressing to paralysis and spreading to other parts of the body, eventually causing total body paralysis. In most patients (about 90%) no apparent genetic cause for their disease has been found, in those cases the disease is called sporadic ALS. In the other 10% a hereditary pattern has been found; familial ALS. In 1993 a mutation was found in the gene for superoxide dismutase 1 (SOD1) which causes ALS in some familial ALS families. By now more than 110 different mutations in the SOD1-gene have been linked to familial ALS and more recently mutations in 5 other genes have been found to cause familial ALS. The discovery of SOD1-mutations has enabled the production of transgenic mutant-SOD1 expressing mice that develop an ALS-like motoneuron disease. These SOD1-mutant mice develop a disease strongly resembling human ALS. These transgenic mice offer the possibility to study all stages of motoneuron death. In this thesis different aspects of ALS in the transgenic mouse model and in cultured motoneurons are studied and discussed.