SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse

Koopmans, Frank; Nierop, Pim van; Andres-Alonso, Maria; Byrnes, Andrea; Cijsouw, Tony; Coba, Marcelo P.; Cornelisse, L. Niels; Farrell, Ryan J.; Goldschmidt, Hana L.; Howrigan, Daniel P.; Hussain, Natasha K.; Imig, Cordelia; Jong, Arthure; Jung, Hwajin; Kohansal-Nodehi, Mahdokht; Kramarz, Barbara; Lipstein, Noa; Lovering, Ruth C.; MacGillavry, Harold D.; Mariano, Vittoria; Mi, Huaiyu; Ninov, Momchil; Osumi-Sutherland, David; Pielot, Rainer; Smalla, Karl‐Heinz; Tang, Haiming; Tashman, Katherine; Toonen, Ruud F.; Verpelli, Chiara; Reig-Viader, Rita; Watanabe, Kyoko; Weering, Jan R.T. van; Achsel, Tilmann; Ashrafi, Ghazaleh; Asi, Nimra; Brown, Tyler C.; Camilli, Pietro De; Feuermann, Marc; Foulger, Rebecca E.; Gaudet, Pascale; Joglekar, Anoushka; Kanellopoulos, Alexandros K.; Malenka, Robert C.; Nicoll, Roger A.; Pulido, Camila; Juan-Sanz, Jaime de; Sheng, Morgan; Südhof, Thomas C.; Tilgner, Hagen; Bagni, Claudia; Bayés, Àlex; Biederer, Thomas; Brose, Nils; Chua, John Jia En; Dieterich, Daniela C.; Gundelfinger, Eckart D.; Hoogenraad, Casper C.; Huganir, Richard L.; Jahn, Reinhard; Kaeser, Pascal S.; Kim, Eunjoon; Kreutz, Michael R.; McPherson, Peter S.; Neale, B. M.; O’Connor, Vincent; Posthuma, Daniëlle; Ryan, Timothy A.; Sala, Carlo; Feng, Guoping; Hyman, Steven E.; Smit, August B.; Verhage, Matthijs

doi:10.1016/j.neuron.2019.05.002

Cited by 691 publications

(803 citation statements)

References 84 publications

Supporting

Mentioning

734

Contrasting

Order By: Relevance

“…Enrichment analyses showed the postsynaptic density as the main altered GO term and the immune response as dominant pathways (supplementary figure 1). To further characterize and confirm the synaptic involvement, we used the SynGO database, which provides an expert-curated resource for synapse function and gene enrichment analysis(23). This analysis confirmed the enrichment of postsynaptic components in our list of differentially expressed isoforms (supplementary…”

mentioning

confidence: 54%

“…Gene ontology and KEGG pathway enrichment analyses were applied using default parameters (minimum overlap=3, p-value cutoff=0.01 and minimum enrichment=1.5) in Metascape 3.0 (22) (http://metascape.org). Synaptic enrichment analyses were also run using the web server SynGO (https://www.syngoportal.org/), which provides an expert-curated resource for synapse function and gene enrichment analysis (23).…”

Section: Data Processingmentioning

confidence: 99%

See 1 more Smart Citation

Characterization of the motor cortex transcriptome supports microgial-related key events in amyotrophic lateral sclerosis

Dols‐Icardo

Montal

Sirisi

et al. 2020

Preprint

View full text Add to dashboard Cite

400w)Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the degeneration of upper and lower motor neurons. A major neuropathological finding in ALS is the coexistence of glial activation and aggregation of the phosphorylated transactive response DNA-binding protein 43-kDa (pTDP43) in the motor cortex at the earliest stages of the disease. Despite this, the transcriptional alterations associated with these pathological changes in this major vulnerable brain region have yet to be fully characterized. Here, we have performed massive RNA sequencing of the motor cortex of ALS (n=11) and healthy controls (HC; n=8). We report extensive RNA expression alterations at gene and isoform levels, characterized by the enrichment of neuroinflammatory and synapse related pathways.The assembly of gene co-expression modules confirmed the involvement of these two principal transcriptomic changes, and showed a strong negative correlation between them.Furthermore, cell-type deconvolution using human single-nucleus RNA sequencing data as reference demonstrated that microglial cells are overrepresented in ALS compared to HC. Importantly, we also show for the first time in the human ALS motor cortex, that microgliosis is mostly driven by the increased proportion of a microglial subpopulation characterized by gene markers overlapping with the recently described disease associated microglia (DAM).Using immunohistochemistry, we further evidenced that this microglial subpopulation is overrepresented in ALS and that variability in pTDP43 aggregation among patients negatively correlates with the proportion of microglial cells. In conclusion, we report that neuroinflammatory changes in ALS motor cortex are dominated by microglia which is concomitant with a reduced expression of postsynaptic transcripts, in which DAM might have a prominent role. Microgliosis therefore represents a promising avenue for therapeutic intervention in ALS.

show abstract

mentioning

confidence: 54%

Section: Data Processingmentioning

confidence: 99%

Characterization of the motor cortex transcriptome supports microgial-related key events in amyotrophic lateral sclerosis

Dols‐Icardo

Montal

Sirisi

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…To investigate the significance of these modules further, we sought to identify whether the enrichment of genes relating to synaptic transmission was driven by genes involved in postsynaptic as compared to pre-synaptic structures. To address this question, we checked for enrichment of genes that have been reliably associated with a specific synaptic structure using the recently released SynGO database (Koopmans et al, 2019). This demonstrated significant enrichment of genes associated with both presynaptic and postsynaptic structures amongst those contained within all four modules of interest (namely the substantia nigra "cyan", putamen "cyan", frontal cortex "lightyellow" and white matter "blue" modules).…”

Section: Resultsmentioning

confidence: 99%

“…Gene modules were functionally annotated with gProfileR R package using Gene Ontology (GO) database without Electronic Inferred Annotations (EIA) and accounting for multiple testing with gSCS (Reimand et al, 2007). Additional functional annotations for modules of interest were generated using the web server SynGO (https://www.syngoportal.org/), which provides an expert-curated resource for synapse function and gene enrichment analysis (Koopmans et al, 2019). All gene set enrichment analyses were performed using default 1 0 settings, with no annotation filters applied and a minimum gene count of three for ontology terms to be included in the overrepresentation analysis.…”

Section: Weighted Gene Co-expression Analysis (Wgcna)mentioning

confidence: 99%

Transcriptomic analysis of dystonia-associated genes reveals functional convergence within specific cell types and shared neurobiology with psychiatric disorders

Mencacci¹,

Reynolds

García-Ruiz

et al. 2020

Preprint

View full text Add to dashboard Cite

Dystonia is a neurological disorder characterized by sustained or intermittent muscle contractions causing abnormal movements and postures, often occurring in absence of any structural brain abnormality. Psychiatric comorbidities, including anxiety, depression, obsessive-compulsive disorder and schizophrenia, are frequent in dystonia patients. While mutations in a fast-growing number of genes have been linked to Mendelian forms of dystonia, the cellular, anatomical, and molecular basis remains unknown for most genetic forms of dystonia, as does its genetic and biological relationship to neuropsychiatric disorders. Here we applied an unbiased systems-biology approach to explore the cellular specificity of all currently known dystonia-associated genes, predict their functional relationships, and test whether dystonia and neuropsychiatric disorders share a genetic relationship. To determine the cellular specificity of dystonia-associated genes in the brain, single-nuclear transcriptomic data derived from mouse brain was used together with expression-weighted cell-type enrichment. To identify functional relationships amongst dystonia-associated genes, we determined the enrichment of these genes in co-expression networks constructed from ten human brain regions. Stratified linkage-disequilibrium score regression was used to test whether co-expression modules enriched for dystonia-associated genes significantly contribute to the heritability of anxiety, major depressive disorder, obsessive-compulsive disorder, schizophrenia, and Parkinson's disease. Dystonia-associated genes were significantly enriched in adult nigral dopaminergic neurons and striatal medium spiny neurons. Furthermore, four of the 220 gene co-expression modules tested were significantly enriched for the dystonia-associated genes. The identified modules were derived from the substantia nigra, putamen, frontal cortex, and white matter, and were all significantly enriched for genes associated with synaptic function. Finally, we demonstrated significant enrichments of the heritability of depression, obsessive-compulsive disorder and schizophrenia, but not anxiety and Parkinson's disease, within the putamen and white matter modules. In conclusion, multiple dystonia-associated genes interact and contribute to pathogenesis likely through dysregulation of synaptic signalling in striatal medium spiny neurons, adult nigral dopaminergic neurons and frontal cortical neurons. Furthermore, the enrichment of the heritability of psychiatric disorders in the co-expression modules enriched for dystonia-associated genes indicates that psychiatric symptoms associated with dystonia are likely to be intrinsic to its pathophysiology. 4

show abstract

“…7d. Five out of 10 clusters have relationship to the synapse (protein localization in synapse, synaptic vesicle transport, dendrite spine morphogenesis, transport along microtubule, junction substrate adhesion), thus we performed enrichment analysis using expert-curated and evidencebased synaptic gene ontology (SynGO) 35 . This revealed that DETs engaged by SD (Ctrl/S vs Ctrl/SD) are highly enriched in synaptic localizations, particularly in postsynapse ( Fig.…”

Section: Neuronal Translatome Regulation By Fxr1 During Sleep Deprivamentioning

confidence: 99%

Fxr1 regulates sleep and synaptic homeostasis

Khlghatyan

Evstratova

Bozoyan

et al. 2019

Preprint

View full text Add to dashboard Cite

The fragile X autosomal homolog 1 (Fxr1) has been GWAS-associated to schizophrenia and insomnia but its contributions to brain functions are unclear. Homeostatic regulation of synaptic strength is essential for the maintenance of brain functions and engages both global and cell autonomous level processes. We used Crispr/Cas9-mediated somatic knockouts, overexpression, neuronal activity recordings and translatome sequencing, to examine the contribution of Fxr1 to cell-autonomous homeostatic synaptic scaling and global-level sleep homeostasis. Our findings indicate that Fxr1 is downregulated during scaling and sleep deprivation via a Gsk3β dependent mechanism. In both conditions, downregulation of Fxr1 is essential for the homeostatic modulation of synaptic strength. Furthermore, overexpression of Fxr1 during sleep deprivation results in altered EEG signatures and reverts changes of translatome profiles.These findings indicate that Fxr1 represents a shared signaling hub linking cell autonomous homeostatic plasticity and system level sleep homeostasis with potential implications for neuropsychiatric illnesses.Khlghatyan et al.

show abstract

SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse

Cited by 691 publications

References 84 publications

Characterization of the motor cortex transcriptome supports microgial-related key events in amyotrophic lateral sclerosis

Characterization of the motor cortex transcriptome supports microgial-related key events in amyotrophic lateral sclerosis

Transcriptomic analysis of dystonia-associated genes reveals functional convergence within specific cell types and shared neurobiology with psychiatric disorders

Fxr1 regulates sleep and synaptic homeostasis

Contact Info

Product

Resources

About