筋萎縮性側索硬化症における亜鉛と小胞体ストレスの役割
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概要
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Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the selective loss of upper and lower motoneurons. Approximately 10% of all ALS cases are genetically inherited, and a mutation in the Cu, Zn superoxide dismutase (SOD1) gene is thought to be a cause of motoneuron dysfunction. Importantly, the motoneuron toxicity appears to result from a toxic gain-of-function mutation in SOD1 and not from the loss of superoxide dismutase activity. Transgenic mice overexpressing several types of SOD1 mutant show the ALS-like phenotype and are widely accepted as animal models of ALS. However, no common toxic mechanism has been identified among these SOD1 mutants. Studies using autopsies of ALS patients or model mouse have suggested multiple causes of ALS including oxidative stress, mitochondrial dysfunction, excitotoxicity, neurofilaments abnormality and protein aggregation. Endoplasmic reticulum (ER) stress mediated motoneuron death is also suggested to be included in the pathogenesis of ALS. ALS-related mutant SOD1 evokes ER stress through the specific interaction with Derlin-1, a component of ER associated degradation (ERAD) machinery, leading to the subsequent motoneuron death. Zinc plays an important role in the function of nervous system and its dyshomeostasis is also thought to be one of the causes of ALS. In fact, zinc accumulation is observed in the brains and the spinal cords of mutant SOD1 transgenic mice. Moreover, zinc chelation extends the life span of these mise. There seems to be relationships between zinc dysregulation and several pathogenic processes of ALS. In this review, we will focus on the pathological role of ER stress and zinc in ALS.
- 日本微量元素学会の論文
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