[The causes and mechanism of selective motor neuron death in amyotrophic lateral sclerosis].

Abstract

Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the selective death of motor neurons in the motor cortex, brain stem and spinal cord. In most cases, the cause of ALS is unknown although in a number of familial ALS cases mutations in the superoxide dismutase 1 (SOD1) gene were discovered. The mechanism underlying the selective motor neuron death is not yet clarified. However, it is clear that excitotoxicity could play a role in the selectivity of the motor neuron death. Excitotoxicity is the phenomenon in which the normal glutamate-mediated communication between neurons is disturbed and ultimately leads to neuronal death. In the first part of this study, we have investigated the intrinsic characteristics of motor neurons that could be responsible for the fact that these cells are extremely sensitive to excitotoxicity. Despite the fact that only the motor neurons die during ALS, it is clear that also other cell types play an important role during this process. In the second part of this study, we have concentrated on the potential role of the microglia. These cells are the macrophages of the brain and they become activated during inflammation. Using minocycline, we have inhibited the activation of the microglia and we have investigated its effect on the start of the disease and on the survival of a mouse model for ALS. Furthermore, we have investigated the cellular mechanism underlying the effect of minocycline. The goal of this research is to get insight into the mechanisms responsible for the selective motor neuron death during ALS and we hope that this information can help in the development of a therapy for this dramatic and incurable disease.