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

International Journal of Molecular Sciences

Páll Karlsson²  Aida Droce²  Jakob M. Moser²  Simon Cuhlmann²  Carolina Ortiz Padilla²  Peter Heimann³  Jörg W. Bartsch¹  Annette F࿌htbauer²  Ernst-Martin F࿌htbauer² 

[1] Department of Neurosurgery, University Marburg, Marburg 35033, Germany; E-Mail:;Molecular Biology and Genetics Department, Aarhus University, Aarhus 8000, Denmark; E-Mails:;Cell Biology Department, Bielefeld University, Bielefeld 33501, Germany; E-Mail:

关键词: Vps54;    wobbler;    ALS;    GARP complex;    retrograde vesicle transport;   

DOI  :  10.3390/ijms140610908

来源: mdpi

【 摘 要 】

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.

【 授权许可】

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