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Widespread aggregation of mutant VAPB associated with ALS does not cause motor neuron degeneration or modulate mutant SOD1 aggregation and toxicity in mice

Qiu, Linghua and Qiao, Tao and Beers, Melissa and Tan, Weijia and Wang, Hongyan and Yang, Bin and Xu, Zuoshang (2013) Widespread aggregation of mutant VAPB associated with ALS does not cause motor neuron degeneration or modulate mutant SOD1 aggregation and toxicity in mice. Molecular Neurodegeneration, 8 . Art. No. 1. ISSN 1750-1326. PMCID PMC3538568.

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Background: A proline-to-serine substitution at position-56 (P56S) of vesicle-associated membrane protein-associated protein B (VAPB) causes a form of dominantly inherited motor neuron disease (MND), including typical and atypical amyotrophic lateral sclerosis (ALS) and a mild late-onset spinal muscular atrophy (SMA). VAPB is an integral endoplasmic reticulum (ER) protein and has been implicated in various cellular processes, including ER stress, the unfolded protein response (UPR) and Ca^(2+) homeostasis. However, it is unclear how the P56S mutation leads to neurodegeneration and muscle atrophy in patients. The formation of abnormal VAPB-positive inclusions by mutant VAPB suggests a possible toxic gain of function as an underlying mechanism. Furthermore, the amount of VAPB protein is reported to be reduced in sporadic ALS patients and mutant SOD1G93A mice, leading to the hypothesis that wild type VAPB plays a role in the pathogenesis of ALS without VAPB mutations. Results: To investigate the pathogenic mechanism in vivo, we generated human wild type (wtVAPB) and mutant VAPB (muVAPB) transgenic mice that expressed the transgenes broadly in the CNS. We observed robust VAPB-positive aggregates in the spinal cord of muVAPB transgenic mice. However, we failed to find an impairment of motor function and motor neuron degeneration. We also did not detect any change in the endogenous VAPB level or evidence for induction of the unfolded protein response (UPR) and coaggregation of VAPA with muVAPB. Furthermore, we crossed these VAPB transgenic mice with mice that express mutant SOD1G93A and develop motor neuron degeneration. Overexpression of neither wtVAPB nor muVAPB modulated the protein aggregation and disease progression in the SOD1G93A mice. Conclusion: Overexpression of VAPBP56S mutant to approximately two-fold of the endogenous VAPB in mouse spinal cord produced abundant VAPB aggregates but was not sufficient to cause motor dysfunction or motor neuron degeneration. Furthermore, overexpression of either muVAPB or wtVAPB does not modulate the course of ALS in SOD1G93A mice. These results suggest that changes in wild type VAPB do not play a significant role in ALS cases that are not caused by VAPB mutations. Furthermore, these results suggest that muVAPB aggregates are innocuous and do not cause motor neuron degeneration by a gain-of-toxicity, and therefore, a loss of function may be the underlying mechanism.

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Additional Information:© 2013 Qiu et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Received: 21 August 2012; Accepted: 29 December 2012; Published: 3 January 2013. The authors thank Ms. Sili Zhou and Dr. Thaya Venugopal for technical assistance, the UMass Transgenic Animal Modeling Core for pronuclear injection and the technical support from the Core Electron Microscopy Facility, which receives support from the National Center for Research Resources (S10RR027897). This work was supported by a grant (5R01NS059708) from National Institute of Neurological Disorders and Stroke to ZX. Authors’ contributions: MB and ZX designed the transgenic constructs. MB constructed and tested the vectors. LQ, MB, TQ, WT, HW, and BY performed experiments. LQ and ZX analyzed the data and wrote the manuscript. All authors have read and approved the final manuscript. Competing interests: The authors declare that they have no competing interests.
Funding AgencyGrant Number
National Center for Research ResourcesS10RR027897
National Institute of Neurological Disorders and Stroke (NINDS)5R01NS059708
Subject Keywords:VAPB, ALS, Motor neuron disease, Neurodegeneration, Transgenic mice
PubMed Central ID:PMC3538568
Record Number:CaltechAUTHORS:20131107-154530979
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Official Citation:Qiu et al.: Widespread aggregation of mutant VAPB associated with ALS does not cause motor neuron degeneration or modulate mutant SOD1 aggregation and toxicity in mice. Molecular Neurodegeneration 2013 8:1
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:42324
Deposited By: Tony Diaz
Deposited On:08 Nov 2013 00:56
Last Modified:03 Oct 2019 05:57

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