ALS-associated P56S-VAPB mutation restrains 3T3-L1 preadipocyte differentiation

Tokutake, Yukako; Gushima, Kazunari; Miyazaki, Honami; Shimosato, Takeshi; Yonekura, Shinichi

doi:10.1016/j.bbrc.2015.03.118

Cited by 11 publications

(12 citation statements)

References 35 publications

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“…In the present study, we co-transfected wt-VAPB and P56-VAPB into C2C12 cells, and found that these proteins were co-localized. This result is in agreement with the results of previous studies using NSC34 cells and 3T3-L1 cells [ 14 , 22 ], and suggests that P56S-VAPB recruits wt-VAPB, thereby inhibiting the function of wt-VAPB.…”

Section: Resultssupporting

confidence: 93%

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

Tokutake

Yamada

Ohata

et al. 2015

IJMS

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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.

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Section: Resultssupporting

confidence: 93%

“…Previous studies on the motor neuron cell line NSC34 and the mouse adipocyte cell line 3T3-L1 have shown that P56S-VAPB aggregates in cells, whereas wt-VAPB distributes uniformly in cells [ 13 , 22 ]. In the present study, we co-transfected wt-VAPB and P56-VAPB into C2C12 cells, and found that these proteins were co-localized.…”

Section: Resultsmentioning

confidence: 99%

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

Tokutake

Yamada

Ohata

et al. 2015

IJMS

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“…Overexpression of wildtype or P56S VAPB in COS-7 cells activates ER stress via IRE1a, and treatment of these cells with the ER stress inhibitor salubrinal reduces the formation of ubiquitinated inclusions (Moumen et al, 2011), implying that VAPB-induced ER stress promotes the formation of inclusions. Overexpression of P56S VAPB also activates the XBP-1/IRE1a pathway in myoblast C2C12 cells, and the ATF4/CHOP pathway in 3T3-L1 cells (Tokutake et al, 2015a,b). Both wildtype and P56S VAPB also inhibit ATF6 expression (Gkogkas et al, 2008).…”

Section: Vapbmentioning

confidence: 99%

Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

Shahheydari

Ragagnin

Walker

et al. 2017

Front. Mol. Neurosci.

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Protein homeostasis, or proteostasis, has an important regulatory role in cellular function. Protein quality control mechanisms, including protein folding and protein degradation processes, have a crucial function in post-mitotic neurons. Cellular protein quality control relies on multiple strategies, including molecular chaperones, autophagy, the ubiquitin proteasome system, endoplasmic reticulum (ER)-associated degradation (ERAD) and the formation of stress granules (SGs), to regulate proteostasis. Neurodegenerative diseases are characterized by the presence of misfolded protein aggregates, implying that protein quality control mechanisms are dysfunctional in these conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that are now recognized to overlap clinically and pathologically, forming a continuous disease spectrum. In this review article, we detail the evidence for dysregulation of protein quality control mechanisms across the whole ALS-FTD continuum, by discussing the major proteins implicated in ALS and/or FTD. We also discuss possible ways in which protein quality mechanisms could be targeted therapeutically in these disorders and highlight promising protein quality control-based therapeutics for clinical trials.

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“…[86][87][88][89][90] Murine models have illustrated loss of function mutations altering the unfolded protein response pathway, reducing functional myotubule formation 91 and this model has been illustrated in human samples elsewhere. 86,92 Additional murine studies have demonstrated progressive hyperactivity and motor impairment due to corticospinal and spinal motor neuron destruction in VABP transgenic mice. 93 Autosomal dominant ALS based on a proline to serine substitution in the VAPB has been linked to nuclear envelope deformity, interrupting the transport of nucleoporin and emerin to the nuclear envelope.…”

Section: P56s-vesicle-associated Membrane Protein-associated Protein mentioning

confidence: 99%

“…94 VABP has also been shown to suppress adipocyte lipid differentiation through alterations in mRNA expression, potentially altering energy metabolism in a subset of ALS patients. 86 However, despite its involvement in intracellular transport, VABP mutations have not demonstrated alterations in protein transport or degradation. 95 Of note, this mutation has not been demonstrated in SALS patients in Sweden, Portugal and Iceland.…”

Section: P56s-vesicle-associated Membrane Protein-associated Protein mentioning

confidence: 99%

Cross-Sectional Survey of Relevant Literatures as to the Current Proposed Disease Mechanisms and Treatments of Amyotrophic Lateral Sclerosis (ALS)

Sanford¹

2015

MJM

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ALS-associated P56S-VAPB mutation restrains 3T3-L1 preadipocyte differentiation

Cited by 11 publications

References 35 publications

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

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

Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

Cross-Sectional Survey of Relevant Literatures as to the Current Proposed Disease Mechanisms and Treatments of Amyotrophic Lateral Sclerosis (ALS)

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