Int. J. Mol. Sci. 2013, 14(6), 10908-10925; doi:10.3390/ijms140610908
Article

Loss of Vps54 Function Leads to Vesicle Traffic Impairment, Protein Mis-Sorting and Embryonic Lethality

1 Molecular Biology and Genetics Department, Aarhus University, Aarhus 8000, Denmark 2 Cell Biology Department, Bielefeld University, Bielefeld 33501, Germany 3 Department of Neurosurgery, University Marburg, Marburg 35033, Germany Current Address: Department of Biotechnology, Chemistry and Environmental Engineering, Aalborg University, Sohngaardsholmsvej 49, Aalborg 9000, Denmark.
* Author to whom correspondence should be addressed.
Received: 3 April 2013; in revised form: 30 April 2013 / Accepted: 3 May 2013 / Published: 24 May 2013
(This article belongs to the Special Issue Regulation of Membrane Trafficking and Its Potential Implications)
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Abstract: The identification of the mutation causing the phenotype of the amyotrophic lateral sclerosis (ALS) model mouse, wobbler, has linked motor neuron degeneration with retrograde vesicle traffic. The wobbler mutation affects protein stability of Vps54, a ubiquitously expressed vesicle-tethering factor and leads to partial loss of Vps54 function. Moreover, the Vps54 null mutation causes embryonic lethality, which is associated with extensive membrane blebbing in the neural tube and is most likely a consequence of impaired vesicle transport. Investigation of cells derived from wobbler and Vps54 null mutant embryos demonstrates impaired retrograde transport of the Cholera-toxin B subunit to the trans-Golgi network and mis-sorting of mannose-6-phosphate receptors and cargo proteins dependent on retrograde vesicle transport. Endocytosis assays demonstrate no difference between wobbler and wild type cells, indicating that the retrograde vesicle traffic to the trans-Golgi network, but not endocytosis, is affected in Vps54 mutant cells. The results obtained on wobbler cells were extended to test the use of cultured skin fibroblasts from human ALS patients to investigate the retrograde vesicle traffic. Analysis of skin fibroblasts of ALS patients will support the investigation of the critical role of the retrograde vesicle transport in ALS pathogenesis and might yield a diagnostic prospect.
Keywords: Vps54; wobbler; ALS; GARP complex; retrograde vesicle transport

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MDPI and ACS Style

Karlsson, P.; Droce, A.; Moser, J.M.; Cuhlmann, S.; Padilla, C.O.; Heimann, P.; Bartsch, J.W.; Füchtbauer, A.; Füchtbauer, E.-M.; Schmitt-John, T. Loss of Vps54 Function Leads to Vesicle Traffic Impairment, Protein Mis-Sorting and Embryonic Lethality. Int. J. Mol. Sci. 2013, 14, 10908-10925.

AMA Style

Karlsson P, Droce A, Moser JM, Cuhlmann S, Padilla CO, Heimann P, Bartsch JW, Füchtbauer A, Füchtbauer E-M, Schmitt-John T. Loss of Vps54 Function Leads to Vesicle Traffic Impairment, Protein Mis-Sorting and Embryonic Lethality. International Journal of Molecular Sciences. 2013; 14(6):10908-10925.

Chicago/Turabian Style

Karlsson, Páll; Droce, Aida; Moser, Jakob M.; Cuhlmann, Simon; Padilla, Carolina O.; Heimann, Peter; Bartsch, Jörg W.; Füchtbauer, Annette; Füchtbauer, Ernst-Martin; Schmitt-John, Thomas. 2013. "Loss of Vps54 Function Leads to Vesicle Traffic Impairment, Protein Mis-Sorting and Embryonic Lethality." Int. J. Mol. Sci. 14, no. 6: 10908-10925.

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