Cohen Syndrome-associated Protein COH1 Physically and Functionally Interacts with the Small GTPase RAB6 at the Golgi Complex and Directs Neurite Outgrowth

Seifert, Wenke; Kühnisch, Jirko; Maritzen, Tanja; Lommatzsch, Stefanie; Hennies, Hans Christian; Bachmann, S.; Horn, Denise; Haucke, Volker

doi:10.1074/jbc.m114.608174

Cited by 72 publications

(81 citation statements)

References 39 publications

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“…VPS13B mutations cause Cohen syndrome, a developmental disorder characterized by mental retardation, microcephaly and facial dysmorphisms [9]. VPS13B has been reported to be a Rab6 effector that controls Golgi integrity [10,11]. VPS13C mutations have recently been described to cause autosomal-recessive early-onset Parkinson’s disease, probably by alteration of mitochondrial morphology and function [12].…”

Section: Introductionmentioning

confidence: 99%

Drosophila Vps13 Is Required for Protein Homeostasis in the Brain

et al. 2017

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Chorea-Acanthocytosis is a rare, neurodegenerative disorder characterized by progressive loss of locomotor and cognitive function. It is caused by loss of function mutations in the Vacuolar Protein Sorting 13A (VPS13A) gene, which is conserved from yeast to human. The consequences of VPS13A dysfunction in the nervous system are still largely unspecified. In order to study the consequences of VPS13A protein dysfunction in the ageing central nervous system we characterized a Drosophila melanogaster Vps13 mutant line. The Drosophila Vps13 gene encoded a protein of similar size as human VPS13A. Our data suggest that Vps13 is a peripheral membrane protein located to endosomal membranes and enriched in the fly head. Vps13 mutant flies showed a shortened life span and age associated neurodegeneration. Vps13 mutant flies were sensitive to proteotoxic stress and accumulated ubiquitylated proteins. Levels of Ref(2)P, the Drosophila orthologue of p62, were increased and protein aggregates accumulated in the central nervous system. Overexpression of the human Vps13A protein in the mutant flies partly rescued apparent phenotypes. This suggests a functional conservation of human VPS13A and Drosophila Vps13. Our results demonstrate that Vps13 is essential to maintain protein homeostasis in the larval and adult Drosophila brain. Drosophila Vps13 mutants are suitable to investigate the function of Vps13 in the brain, to identify genetic enhancers and suppressors and to screen for potential therapeutic targets for Chorea-Acanthocytosis.

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Section: Introductionmentioning

confidence: 99%

Drosophila Vps13 Is Required for Protein Homeostasis in the Brain

et al. 2017

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“…Wenke Seifert et al have reported COH1 regulates the differentiation and integration of neurons into a functional network. Reduced COH1 attachment to the Golgi membrane will inhibits efficient polarization and targeted membrane transport toward the developing axon (Seifert et al, 2015). Laurence Duplomb et al have verified that VPS13B plays a major role in the function of the Golgi apparatus associated with major alterations in protein glycosylation in CS patients with VPS13B mutations (Duplomb et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Gene analysis: A rare gene disease of intellectual deficiency‐Cohen syndrome

Yang

Hou

et al. 2018

Intl J of Devlp Neuroscience

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Cohen syndrome is a rare, genetic, connective-tissue disorder, which is caused by mutations in the gene COH1 (VPS13B, Vacuolar Protein Sorting 13 Homolog B) at the chromosome 8q22. The disease is rare reported, which major clinical features include postnatal microcephaly, obesity, short stature, intellectual disability, progressive retinal dystrophy, intermittent neutropenia and many other unusual facial feature. We report four patients in China who were diagnosed with Cohen syndrome by genetic testing and clinical manifestations. At the same time, we review the related literature, and further expound the molecular mechanism of the disease, a variety of clinical manifestations, treatment and prognosis.

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“…If human VPS13 proteins have evolved different localization mechanisms to target distinct contact sites, the VAB domains of some paralogs may have lost their adaptor binding function. This could be true for VPS13B, which has a poorly conserved VAB domain and instead localizes to Golgi membranes through its C-terminus (52). The divergent VAB domain of VPS13B has serine residues in the place of conserved asparagines in the 2 nd and 3 rd VAB domain repeats.…”

Section: The Role Of Vab Domain In Human Vps13 Proteinsmentioning

confidence: 99%

A VPS13D spastic ataxia mutation disrupts the conserved adaptor binding site in yeast Vps13

Dziurdzik

Bean²,

Davey

et al. 2019

Preprint

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Mutations in each of the four human VPS13 (VPS13A-D) proteins are associated with distinct neurological disorders: chorea-acanthocytosis, Cohen syndrome, early-onset Parkinson's disease and spastic ataxia. Recent evidence suggests that the different VPS13 paralogs transport lipids between organelles at different membrane contact sites. How each VPS13 isoform is targeted to organelles is not known. We have shown that the localization of yeast Vps13 protein to membranes requires a conserved six-repeat region, the Vps13 Adaptor Binding (VAB) domain, which binds to organelle-specific adaptors.Here, we use a systematic mutagenesis strategy to determine the role of each repeat in recognizing each known adaptor. Our results show that mutation of invariant asparagines in repeats 1 and 6 strongly impact the binding all adaptors and block Vps13 membrane recruitment. However, we find that repeats 5 to 6 are sufficient for localization and interaction with adaptors. This supports a model where a single adaptor binding site is found in the last two repeats of the VAB domain, while VAB domain repeat 1 may help maintain domain conformation. Importantly, a disease-causing mutation in VPS13D, which maps to the highly conserved asparagine residue in repeat 6, blocks adaptor binding and Vps13 membrane recruitment when modeled in yeast. Our findings are consistent with a conserved adaptor binding role for the VAB domain and suggests the presence of as-yet-unidentified adaptors in both yeast and humans.3

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Cohen Syndrome-associated Protein COH1 Physically and Functionally Interacts with the Small GTPase RAB6 at the Golgi Complex and Directs Neurite Outgrowth

Cited by 72 publications

References 39 publications

Drosophila Vps13 Is Required for Protein Homeostasis in the Brain

Drosophila Vps13 Is Required for Protein Homeostasis in the Brain

Gene analysis: A rare gene disease of intellectual deficiency‐Cohen syndrome

A VPS13D spastic ataxia mutation disrupts the conserved adaptor binding site in yeast Vps13

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