Characterization of Vps13b-mutant mice reveals neuroanatomical and behavioral phenotypes with females less affected

Montillot, Charlotte; Skutunova, Emilia; Ayushma,; Dubied, Morgane; Lahmar, Adam; Nguyen, Sylvie; Peerally, Benazir; Prin, Fabrice; Duffourd, Yannis; Thauvin-Robinet, Christel; Duplomb, Laurence; Wang, Heng; Ansar, Muhammad; Faivre, Laurence; Navarro, Nicolas; Minocha, Shilpi; Collins, Stephan C.; Yalcin, Binnaz

doi:10.1016/j.nbd.2023.106259

Cited by 3 publications

(4 citation statements)

References 56 publications

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“…is required for the growth of the acrosomal membrane of sperm, a Golgi complex-derived membrane critical for fertilization, consistent with the proposed lipid transport role of VPS13 family proteins in membrane expansion, and absence of Vps13b in mice leads to male sterility (Da Costa et al, 2019) and neuroanatomical phenotypes (Montillot et al, 2023). However, the precise localization of VPS13B within the Golgi complex, and thus the sites where its lipid transport function is likely achieved, remains unknown.…”

supporting

confidence: 62%

“…In conclusion, our studies provide new insight into the site of action of VPS13B, suggest the possibility that this protein may mediate bridge-like lipid transport between Golgi subcompartments, and identify FAM177A1 as one of its potential functional partners. They provide a foundation for further investigations of the cellular (Seifert et al, 2011;Duplomb et al, 2014;Zorn et al, 2022) and organismal (Da Costa et al, 2019;Kim et al, 2019;Gabrielle et al, 2021;Montillot et al, 2023) phenotypes produced by VPS13B loss-of-function.…”

Section: A Partnership Of Fam177a1 and Vps13b In Zebrafishmentioning

confidence: 99%

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VPS13B is localized at the cis-trans Golgi complex interface and is a functional partner of FAM177A1

Ugur,

Schueder,

Shin

et al. 2023

Preprint

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Mutations in VPS13B, a member of a protein family implicated in bulk lipid transport between adjacent membranes, cause Cohen syndrome. VPS13B is known to be concentrated in the Golgi complex, but its precise location within this organelle and thus the site(s) where it achieves lipid transport remains unclear. Here we show that VPS13B is localized at the interface between cis and trans Golgi sub-compartments and that Golgi complex re-formation after Brefeldin A (BFA) induced disruption is delayed inVPS13BKO cells. This delay is phenocopied by loss of FAM177A1, a Golgi complex protein of unknown function reported to be a VPS13B interactor and whose mutations also result in a developmental disorder. In zebrafish, thevps13borthologue, not previously annotated in this organism, genetically interacts withfam177a1. Collectively, these findings raise the possibility that bulk lipid transport by VPS13B may play a role in expanding Golgi membranes and that VPS13B may be assisted in this function by FAM177A1.

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supporting

confidence: 62%

Section: A Partnership Of Fam177a1 and Vps13b In Zebrafishmentioning

confidence: 99%

VPS13B is localized at the cis-trans Golgi complex interface and is a functional partner of FAM177A1

Ugur,

Schueder,

Shin

et al. 2023

Preprint

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“…The third model, denoted as Vps13b tm1.2Ics , is the most extensively characterized model of CS. This model involved the deletion of exon 4 in the Vps13b gene ( Da Costa et al, 2020 ; Lhussiez et al, 2020 ; Bonfante et al, 2021 ; Montillot et al, 2023 ). Unlike the two previous mouse models, it was developed on a mixed genetic background comprising C57BL/6N and C57BL/6J strains of mice, which are known to have genetic and phenotypic divergences ( Simon et al, 2013 ).…”

Section: Animal Models Of Cohen Syndromementioning

confidence: 99%

“…Furthermore, brain anatomy and behavior were comprehensively assessed in Vps13b tm1.2Ics mice ( Montillot et al, 2023 ). About half of the KO mice died during the first week of life, while the remaining mice had normal lifespan and presented core phenotypes of CS, including microcephaly, growth delay, hypotonia, altered memory, and enhanced sociability.…”

Section: Animal Models Of Cohen Syndromementioning

confidence: 99%

Exploring the pathological mechanisms underlying Cohen syndrome

Vacca,

Yalcin,

Ansar

2024

Front. Neurosci.

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Cohen Syndrome (CS) is a rare autosomal recessive disorder caused by biallelic mutations in the VPS13B gene. It is characterized by multiple clinical features, including acquired microcephaly, developmental delay, intellectual disability, neutropenia, and retinal degeneration. VPS13B is part of the bridge-like lipid transport (BLTP) protein family, which in mammals also includes VPS13A, -C, and -D. The proteins of this family are peripheral membrane proteins with different sub-cellular localization, but all share similar structural features and have been proposed to act as lipid transport proteins at organellar membrane contact sites. VPS13B is localized at the Golgi apparatus and is essential for the maintenance of organelle architecture. Here we present a review of the experimental data on the function of the protein at the cellular level, discussing the potential link with disease phenotype and review the studies on animal models recapitulating features of the human disease.

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DNA Damage and Parkinson’s Disease

Pfeifer

2024

IJMS

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The etiology underlying most sporadic Parkinson’s’ disease (PD) cases is unknown. Environmental exposures have been suggested as putative causes of the disease. In cell models and in animal studies, certain chemicals can destroy dopaminergic neurons. However, the mechanisms of how these chemicals cause the death of neurons is not understood. Several of these agents are mitochondrial toxins that inhibit the mitochondrial complex I of the electron transport chain. Familial PD genes also encode proteins with important functions in mitochondria. Mitochondrial dysfunction of the respiratory chain, in combination with the presence of redox active dopamine molecules in these cells, will lead to the accumulation of reactive oxygen species (ROS) in dopaminergic neurons. Here, I propose a mechanism regarding how ROS may lead to cell killing with a specificity for neurons. One rarely considered hypothesis is that ROS produced by defective mitochondria will lead to the formation of oxidative DNA damage in nuclear DNA. Many genes that encode proteins with neuron-specific functions are extraordinary long, ranging in size from several hundred kilobases to well over a megabase. It is predictable that such long genes will contain large numbers of damaged DNA bases, for example in the form of 8-oxoguanine (8-oxoG), which is a major DNA damage type produced by ROS. These DNA lesions will slow down or stall the progression of RNA polymerase II, which is a term referred to as transcription stress. Furthermore, ROS-induced DNA damage may cause mutations, even in postmitotic cells such as neurons. I propose that the impaired transcription and mutagenesis of long, neuron-specific genes will lead to a loss of neuronal integrity, eventually leading to the death of these cells during a human lifetime.

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Characterization of Vps13b-mutant mice reveals neuroanatomical and behavioral phenotypes with females less affected

Cited by 3 publications

References 56 publications

VPS13B is localized at the cis-trans Golgi complex interface and is a functional partner of FAM177A1

VPS13B is localized at the cis-trans Golgi complex interface and is a functional partner of FAM177A1

Exploring the pathological mechanisms underlying Cohen syndrome

DNA Damage and Parkinson’s Disease

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