ER Stress and Unfolded Protein Response in Amyotrophic Lateral Sclerosis

被引:126
作者
Kanekura, Kohsuke [1 ,2 ]
Suzuki, Hiroaki [1 ,2 ,3 ]
Aiso, Sadakazu [2 ]
Matsuoka, Masaaki [1 ]
机构
[1] Keio Univ, Dept Cell Biol & Neurosci, Sch Med, Shinjuku Ku, Tokyo 1608582, Japan
[2] Keio Univ, Dept Anat, Tokyo 1608582, Japan
[3] Japan Soc Promot Sci Res Fellow, Tokyo, Japan
基金
日本学术振兴会;
关键词
Amyotrophic lateral sclerosis; ER stress; Unfolded protein response; ENDOPLASMIC-RETICULUM STRESS; CU; ZN SUPEROXIDE-DISMUTASE; MOTOR-NEURON DEGENERATION; SPINAL-CORD; MEMBRANE-PROTEIN; WILD-TYPE; GOLGI-APPARATUS; MUTANT SOD1; CELL-DEATH; ZN-SUPEROXIDE DISMUTASE;
D O I
10.1007/s12035-009-8054-3
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Several theories on the pathomechanism of amyotrophic lateral sclerosis (ALS) have been proposed: misfolded protein aggregates, mitochondrial dysfunction, increased glutamate toxicity, increased oxidative stress, disturbance of intracellular trafficking, and so on. In parallel, a number of drugs that have been developed to alleviate the putative key pathomechanism of ALS have been under clinical trials. Unfortunately, however, almost all studies have finished unsuccessfully. This fact indicates that the key ALS pathomechanism still remains a tough enigma. Recent studies with autopsied ALS patients and studies using mutant SOD1 (mSOD1) transgenic mice have suggested that endoplasmic reticulum (ER) stress-related toxicity may be a relevant ALS pathomechanism. Levels of ER stress-related proteins were upregulated in motor neurons in the spinal cords of ALS patients. It was also shown that mSOD1, translocated to the ER, caused ER stress in neurons in the spinal cord of mSOD1 transgenic mice. We recently reported that the newly identified ALS-causative gene, vesicle-associated membrane protein-associated protein B (VAPB), plays a pivotal role in unfolded protein response (UPR), a physiological reaction against ER stress. The ALS-linked P56S mutation in VAPB nullifies the function of VAPB, resulting in motoneuronal vulnerability to ER stress. In this review, we summarize recent advances in research on the ALS pathomechanism especially addressing the putative involvement of ER stress and UPR dysfunction.
引用
收藏
页码:81 / 89
页数:9
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