ALS-Linked P56S-VAPB Mutation Impairs the Formation of Multinuclear Myotube in C2C12 Cells

被引:19
作者
Tokutake, Yukako [1 ]
Yamada, Keita [2 ]
Ohata, Masaki [2 ]
Obayashi, Yoshihito [2 ]
Tsuchiya, Megumi [2 ]
Yonekura, Shinichi [1 ,2 ,3 ]
机构
[1] Shinshu Univ, Interdisciplinary Grad Sch Sci & Technol, Nagano 3994598, Japan
[2] Shinshu Univ, Grad Sch Agr, Nagano 3994598, Japan
[3] Shinshu Univ, ICCER, Inst Biomed Sci, Dept Interdisciplinary Genome Sci & Cell Metab, Nagano 3994598, Japan
关键词
amyotrophic lateral sclerosis; satellite cells; vesicle-associated membrane protein associated protein B; differentiation; unfolded protein response; UNFOLDED PROTEIN RESPONSE; IRE1-ALPHA-XBP1; PATHWAY; SKELETAL-MUSCLE; MOTOR-NEURONS; ER STRESS; DIFFERENTIATION; VAPB; MUTANT; DISEASE; PROLIFERATION;
D O I
10.3390/ijms160818628
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder that affects upper and lower motor neurons. Since motor neurons target skeletal muscles, the maintenance system of muscles is disturbed in ALS; however, the mechanism by which this occurs is unknown. In the present study, we investigated the effects of ALS-associated P56S-vesicle-associated membrane protein-associated protein B (VAPB) (P56S-VAPB) on the IRE1-XBP1 pathway, which is involved in the unfolded protein response (UPR) of the mouse myoblast cell line (C2C12 cells). Experiments with C2C12 cells transfected with wild-type wt-VAPB and P56S-VAPB expression vectors showed reduced myotube formation and aberrant myonuclear position in cells expressing P56S-VAPB. Activity of the IRE1-XBP1 pathway in the cells visualized with the ERAI system revealed that the pathway was disrupted in cells expressing P56S-VAPB, whereas the IRE1-XBP1 pathway activity was enhanced in the differentiation process of normal C2C12 cells. These results suggest that disruption of the IRE1-XBP1 pathway is a cause for the reduced myotube formation in P56S-VAPB-expressing cells. The expression level of the VAPB protein has been reported to be reduced in the neurons of patients with ALS. Therefore, it is expected that the IRE1-XBP1 pathway is also impaired in muscle tissues of patients with ALS, which causes a disturbance in the muscle maintenance system.
引用
收藏
页码:18628 / 18641
页数:14
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