Golgipathies in Neurodevelopment: A New View of Old Defects

Rasika, Sowmyalakshmí; Passemard, Sandrine; Verloès, Alain; Gressèns, Pierre; Ghouzzi, Vincent El

doi:10.1159/000497035

Cited by 42 publications

(60 citation statements)

References 214 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As such, their function is critical in development. Defects in different subunits have been implicated in both animal models and human genetic disorders (2,4,5). Here, we report a coatopathy due to pathogenic variants in COPB2 in five unrelated families.…”

Section: Discussionmentioning

confidence: 86%

“…Likewise, Copb2 -/mouse embryos did not show microcephaly or brain anatomical abnormalities, and the heterozygous mice had no observed neurological phenotype (http://www.mousephenotype.org/). Interestingly, developmental delay, with or without microcephaly, had been reported in coatopathies and other disorders related to vesicular transport dysfunction (2,4,5).…”

Section: Copb2 Mutant Zebrafish Embryos Show Delayed Mineralizationmentioning

confidence: 99%

“…Abnormal vesicular transport also affects post-translational modifications (specifically glycosylation) of secreted proteins at the Golgi complex and may alter the extracellular matrix composition. Although this can affect multiple organ systems, the central nervous system is most frequently affected, with individuals typically manifesting with microcephaly and developmental delay (2,4,5).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

COPB2haploinsufficiency causes a coatopathy with osteoporosis and developmental delay

Marom¹,

Burrage²,

Clément³

et al. 2020

Preprint

View full text Add to dashboard Cite

Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2, a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures and developmental delay of variable severity. Because the role of COPB2 in bone has not been characterized, we studied the effect of COPB2 deficiency on skeletal development in mice and zebrafish. Copb2+/− mice showed low bone mass and decreased bone strength. In zebrafish, larvae carrying a copb2 heterozygous frameshift variant showed delayed mineralization. copb2-null embryos showed endoplasmic reticulum (ER) and Golgi disorganization, and embryonic lethality. COPB2 siRNA-treated fibroblasts showed delayed collagen trafficking with retention of type I collagen in the ER and Golgi, and altered distribution of Golgi markers. Our data suggest that COPB2 haploinsufficiency leads to disruption of intracellular collagen trafficking and osteoporosis, which may improve with ascorbic acid supplementation. This work highlights the role of COPI complex as a critical regulator of bone mass and identifies a new form of coatopathy due to COPB2 deficiency.

show abstract

Section: Discussionmentioning

confidence: 86%

Section: Copb2 Mutant Zebrafish Embryos Show Delayed Mineralizationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

COPB2haploinsufficiency causes a coatopathy with osteoporosis and developmental delay

Marom¹,

Burrage²,

Clément³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The link of RAB2 dependent secretory Golgi function to the presynaptic TV biogenesis might help in the future to better understand RAB2 related neurodevelopmental defects, e.g. memory defects prefrontal morphology in human (Li et al, 2015), autism spectrum disorders (ASDs) or schizophrenia (SCZ) Takata et al, 2016), but also connect to Golgi-pathway related neurodegenerative diseases (Rasika et al, 2018). (V) Release kinetics with eEJC tau were not altered (wt: 5.567 ± 0.1846 ms, n=10; rab2 -/-: 5.042 ± 0.2695 ms, n=11), neither (W) short-term plasticity with a 10 ms paired-pulse ratio (wt: 0.7974 ± 0.06262, n=10; rab2 -/-: 0.8388 ± 0.05969, n=10).…”

Section: Discussionmentioning

confidence: 99%

Presynaptic precursor vesicles originate from thetrans-Golgi network, promoted by the small GTPase RAB2

Goetz

Puchkov

Luetzkendorf

et al. 2020

Preprint

View full text Add to dashboard Cite

Reliable delivery of presynaptic material, including active zone and synaptic vesicle proteins from neuronal somata to synaptic terminals is prerequisite for faithful synaptogenesis and neurotransmission. However, molecular mechanisms controlling the somatic assembly of presynaptic precursors remain insufficiently understood. Here we show that in mutants of the small GTPase RAB2 active zone and synaptic vesicle proteins accumulated in the neuronal somata at the trans-Golgi network and were consequently depleted at synaptic terminals, provoking neurotransmission deficits. The ectopic presynaptic material accumulations consisted of heterogeneous vesicles and short tubules of 40x60 nm and segregated in subfractions either positive for active zone proteins or co-positive for synaptic vesicle proteins and LAMP1, a lysosomal membrane protein. Genetically, rab2 behaved epistatic over arl8, a lysosomal adaptor controlling axonal export of precursors. Collectively, we here identified a Golgi-associated assembly sequence in presynaptic precursor vesicle biogenesis controlled by RAB2 dependent membrane remodelling and protein sorting at the trans-Golgi.

show abstract

“…High-throughput sequencing has allowed to more readily capture variations causing subtle or atypical phenotypes, especially in NDDs (Hu et al, 2014). Recently, the role of membrane trafficking during brain development and maturation has been highlighted with a central contribution played by the Golgi apparatus and its impact on key processes : neurogenesis, neuronal migration, myelination and maturation of postmitotic neurons ( (Passemard et al, 2017;Rasika et al, 2019). In particular, the Golgi-associated retrograde protein (GARP) acts in promoting the retrograde fusion of endosome-derived carriers with the trans-Golgi network (TGN) (Bonifacino and Hierro, 2011;Conibear and Stevens, 2000;Perez-Victoria et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

VPS51 biallelic variants cause microcephaly with brain malformations: A confirmatory report

Uwineza

Caberg

Hitayezu

et al. 2019

European Journal of Medical Genetics

Self Cite

View full text Add to dashboard Cite

Genome-wide linkage analysis and whole exome sequencing undertaken in two siblings with delayed psychomotor development, absent speech, severe intellectual disability and postnatal microcephaly, revealed a homozygous intragenic deletion in VPS51, which encodes the vacuolar protein sortingassociated protein, one the four subunits of the GARP and EARP complexes that promotes the fusion of endosome-derived vesicles with the trans-Golgi network (GARP) and recycling endosomes (EARP). This observation supports a pathogenic effect of VPS51 variants, which has only been reported previously once, in a child with microcephaly. It confirms the key role of membrane trafficking in normal brain development and homeostasis.

show abstract

Golgipathies in Neurodevelopment: A New View of Old Defects

Cited by 42 publications

References 214 publications

COPB2haploinsufficiency causes a coatopathy with osteoporosis and developmental delay

COPB2haploinsufficiency causes a coatopathy with osteoporosis and developmental delay

Presynaptic precursor vesicles originate from thetrans-Golgi network, promoted by the small GTPase RAB2

VPS51 biallelic variants cause microcephaly with brain malformations: A confirmatory report

Contact Info

Product

Resources

About