Pathogenese der amyotrophen Lateralsklerose

More than 100 years after the first account of amyotrophic lateral sclerosis (ALS) pathogenesis of the disease remains still an unresolved issue. Several pathogenetic hypotheses have been put forward to account for the selective neurodegeneration of motor neurons in amyotrophic lateral sclerosis. Excitotoxicity is an important mechanism leading to cell death in various conditions. Over the past few years, evidence has accumulated that supports the hypothesis that excitotoxic damage contributes to selective motor neuron death in amyotrophic lateral sclerosis. The capacity of glutamate transporters is reduced in affected CNS regions, possibly leading to an accumulation of glutamate in the synaptic cleft. The cause of this abnormality has not been cleared. Oxidative stress is an other mechanism thought to contribute to a variety of processes such as ischaemic cell death, aging and neurodegenerative disease. Increased markers of oxidative damage have been demonstrated in familial and sporadic amyotrophic lateral sclerosis. Other factors such as derangement of neurofilaments and, possibly in some patients, even immunological abnormalities may also be important. Research on the mechanisms of cell damage in SOD-1 mutations has yielded additional insight into the pathogenesis of both familial and sporadic amyotrophic lateral sclerosis. SOD-1 mutations account for 10 to 20% of familial ALS cases and a small minority of patients with sporadic amyotrophic lateral sclerosis, but the development of transgenic mice has generated an excellent tool for both pathogenetic and therapeutic research. SOD-1 is important in the detoxification of reactive oxygen species but it is apparent that not the loss of enzymatic function causes motor neuron death. It is rather the gain in a new neurotoxic property of the mutant SOD-1 that results in motor neuron damage. As there exists experimental evidence for all of the above-discussed mechanisms, it is probable that not a single pathogenetic event leads to motor neuron death in amyotrophic lateral sclerosis but rather a cascade of linked mechanisms.