Synaptogenesis Is Modulated by Heparan Sulfate in<i>Caenorhabditis elegans</i>

Lázaro-Peña, María I.; Díaz-Balzac, Carlos A.; Bülow, Hannes E.; Emmons, Scott W.

doi:10.1534/genetics.118.300837

Cited by 23 publications

(19 citation statements)

References 67 publications

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“…In addition, hse-5 may regulate the connectivity of neurons controlling stereotyped behaviors such as C . elegans male mating [39]. The human homolog of hse-5 , GLCE , encodes the heparan sulfate-modifying enzyme glucuronic acid epimerase (GLCE).…”

Section: Resultsmentioning

confidence: 99%

Genome wide analysis reveals heparan sulfate epimerase modulates TDP-43 proteinopathy

et al. 2019

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Pathological phosphorylated TDP-43 protein (pTDP) deposition drives neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). However, the cellular and genetic mechanisms at work in pathological TDP-43 toxicity are not fully elucidated. To identify genetic modifiers of TDP-43 neurotoxicity, we utilized a Caenorhabditis elegans model of TDP-43 proteinopathy expressing human mutant TDP-43 pan-neuronally (TDP-43 tg). In TDP-43 tg C. elegans, we conducted a genome-wide RNAi screen covering 16,767 C. elegans genes for loss of function genetic suppressors of TDP-43-driven motor dysfunction. We identified 46 candidate genes that when knocked down partially ameliorate TDP-43 related phenotypes; 24 of these candidate genes have conserved homologs in the human genome. To rigorously validate the RNAi findings, we crossed the TDP-43 transgene into the background of homozygous strong genetic loss of function mutations. We have confirmed 9 of the 24 candidate genes significantly modulate TDP-43 transgenic phenotypes. Among the validated genes we focused on, one of the most consistent genetic modifier genes protecting against pTDP accumulation and motor deficits was the heparan sulfate-modifying enzyme hse-5, the C. elegans homolog of glucuronic acid epimerase (GLCE). We found that knockdown of human GLCE in cultured human cells protects against oxidative stress induced pTDP accumulation. Furthermore, expression of glucuronic acid epimerase is significantly decreased in the brains of FTLD-TDP cases relative to normal controls, demonstrating the potential disease relevance of the candidate genes identified. Taken together these findings nominate glucuronic acid epimerase as a novel candidate therapeutic target for TDP-43 proteinopathies including ALS and FTLD-TDP.

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Section: Resultsmentioning

confidence: 99%

Genome wide analysis reveals heparan sulfate epimerase modulates TDP-43 proteinopathy

et al. 2019

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“…Notably, we noticed that a series of candidates identified as area-specific genes (NDST3, GPC5, GPC6, HS6ST2, HPSE2, SULF2 and LRRTM4) are involved in heparan-sulfate proteoglycan (HSPG) pathways. HSPG family plays an important role in regulating axon guidance, synaptic organization and synaptic specificity (34)(35)(36).…”

Section: Single-cell Analysis Resolves the Area-specific Transcriptiomentioning

confidence: 99%

Spatially resolved gene regulatory and disease vulnerability map of the adult Macaque cortex

Lei

Cheng

et al. 2020

Preprint

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Non-human primates (NHP) provide a unique opportunity to study human neurological diseases, yet detailed characterization of the cell types and transcriptional regulatory features in the NHP brain is lacking. We applied a combinatorial indexing assay, sci-ATAC-seq, as well as single-nuclei RNA-seq, to profile chromatin accessibility in 43,793 single cells and transcriptomics in 11,477 cells, respectively, from prefrontal cortex, primary motor cortex and the primary visual cortex of adult cynomolgus monkey Macaca fascularis. Integrative analysis of these two datasets, resolved regulatory elements and transcription factors that specify cell type distinctions, and discovered area-specific diversity in chromatin accessibility and gene expression within excitatory neurons. We also constructed the dynamic landscape of chromatin accessibility and gene expression of oligodendrocyte maturation to characterize adult remyelination. Furthermore, we identified cell type-specific enrichment of differentially spliced gene isoforms and disease-associated single nucleotide polymorphisms. Our datasets permit integrative exploration of complex regulatory dynamics in macaque brain tissue at single-cell resolution.

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“…GeneNetwork, which uses gene co-regulation to predict pathway membership by integrating 31,499 public RNA-seq sample, provided predictions consistent to ours (Supplementary Tables S3A, B, Supplementary file), since "transmission across synapses" appeared as a major function deduced from the Hs3st2 and Hs3st4 reactomes. Given in addition that loss of 3-O-sulfation in invertebrates generate abnormal synaptic vesicles distribution 9 , and our finding of an association between G2 and the ontology term "synaptic vesicle clustering", we tested the effect of G2 on neural activity and exocytosis.…”

Section: Input Concentration 2× Proteinmentioning

confidence: 99%

3-O-sulfated heparan sulfate interactors target synaptic adhesion molecules from neonatal mouse brain and inhibit neural activity and synaptogenesis in vitro

Maïza

Sidahmed-Adrar

Michel

et al. 2020

Sci Rep

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Heparan sulfate (HS) chains, covalently linked to heparan sulfate proteoglycans (HSPG), promote synaptic development and functions by connecting various synaptic adhesion proteins (AP). HS binding to AP could vary according to modifications of HS chains by different sulfotransferases. 3-O-sulfotransferases (Hs3sts) produce rare 3-O-sulfated HSs (3S-HSs), of poorly known functions in the nervous system. Here, we showed that a peptide known to block herpes simplex virus by interfering with 3S-HSs in vitro and in vivo (i.e. G2 peptide), specifically inhibited neural activity, reduced evoked glutamate release, and impaired synaptic assembly in hippocampal cell cultures. A role for 3S-HSs in promoting synaptic assembly and neural activity is consistent with the synaptic interactome of G2 peptide, and with the detection of Hs3sts and their products in synapses of cultured neurons and in synaptosomes prepared from developing brains. Our study suggests that 3S-HSs acting as receptors for herpesviruses might be important regulators of neuronal and synaptic development in vertebrates.

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Synaptogenesis Is Modulated by Heparan Sulfate inCaenorhabditis elegans

Abstract: The nervous system relies on synapses to transmit information between neurons and thereby direct behavior, but how the correct synaptic connections are genetically specified is poorly understood. By genetically ablating enzymes that modify heparan sulfate...

Cited by 23 publications

References 67 publications

Genome wide analysis reveals heparan sulfate epimerase modulates TDP-43 proteinopathy

Genome wide analysis reveals heparan sulfate epimerase modulates TDP-43 proteinopathy

Spatially resolved gene regulatory and disease vulnerability map of the adult Macaque cortex

3-O-sulfated heparan sulfate interactors target synaptic adhesion molecules from neonatal mouse brain and inhibit neural activity and synaptogenesis in vitro

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