Neuronal pentraxins as biomarkers of synaptic activity: from physiological functions to pathological changes in neurodegeneration

José, Nerea Gómez de San; Massa, Federico; Halbgebauer, Steffen; Oeckl, Patrick; Steinacker, Petra; Otto, Markus

doi:10.1007/s00702-021-02411-2

Cited by 51 publications

(33 citation statements)

References 182 publications

(427 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They are synaptic proteins that associate and form heteromultimers functionally implicated in the clustering of glutamate receptors and therefore, play vital roles in synaptic function and plasticity. 31 The pentraxins have recently gained attention as potential synaptic pathology biomarkers in AD, for which their concentrations have repeatedly been found to be lower [32][33][34][35][36][37] compared to controls. Still, few studies have been performed on other neurodegenerative diseases such as PD and atypical parkinsonism.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal FluidBiomarkers of Synaptic Dysfunction are Altered in Parkinson's Disease and Related Disorders

et al. 2022

View full text Add to dashboard Cite

A BS TRACT: Background: Synaptic dysfunction and degeneration are central contributors to the pathogenesis and progression of parkinsonian disorders. Therefore, identification and validation of biomarkers reflecting pathological synaptic alterations are greatly needed and could be used in prognostic assessment and to monitor treatment effects. Objective: To explore candidate biomarkers of synaptic dysfunction in Parkinson's disease (PD) and related disorders. Methods: Mass spectrometry was used to quantify 15 synaptic proteins in two clinical cerebrospinal fluid (CSF) cohorts, including PD (n 1 = 51, n 2 = 101), corticobasal degeneration (CBD) (n 1 = 11, n 2 = 3), progressive supranuclear palsy (PSP) (n 1 = 22, n 2 = 21), multiple system atrophy (MSA) (n 1 = 31, n 2 = 26), and healthy control (HC) (n 1 = 48, n 2 = 30) participants, as well as Alzheimer's disease (AD) (n 2 = 23) patients in the second cohort.Results: Across both cohorts, lower levels of the neuronal pentraxins (NPTX; 1, 2, and receptor) were found in PD, MSA, and PSP, compared with HC. In MSA and PSP, lower neurogranin, AP2B1, and complexin-2 levels compared with HC were observed. In AD, levels of 14-3-3 zeta/delta, beta-and gamma-synuclein were higher compared with the parkinsonian disorders. Lower pentraxin

show abstract

Section: Discussionmentioning

confidence: 99%

Cerebrospinal FluidBiomarkers of Synaptic Dysfunction are Altered in Parkinson's Disease and Related Disorders

et al. 2022

View full text Add to dashboard Cite

show abstract

“…The presence of coiled-coil N-terminal regions has also been predicted in the neuronal long pentraxins NPTX1 and NPTX2, which also contain three N-terminal cysteine residues per monomer involved in the oligomerization of distinct subunits ( 27 ). The other human long pentraxins, NPTXR and PTX4, are also predicted to have coiled-coil domains in their N-terminal regions ( 28 ), with AlphaFold concurrently predicting a large proportion of α-helical secondary structure at this region in both proteins ( 14 ). Our model of PTX3 now strongly implies that PTX4, NPTX1, NPTX2, and NPTXR also utilize their N-terminal coiled-coil domains to form novel pentraxin oligomerization states.…”

Section: Resultsmentioning

confidence: 99%

PTX3 structure determination using a hybrid cryoelectron microscopy and AlphaFold approach offers insights into ligand binding and complement activation

Noone

Dijkstra

Klugt

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Pattern recognition molecules (PRMs) form an important part of innate immunity, where they facilitate the response to infections and damage by triggering processes such as inflammation. The pentraxin family of soluble PRMs comprises long and short pentraxins, with the former containing unique N-terminal regions unrelated to other proteins or each other. No complete high-resolution structural information exists about long pentraxins, unlike the short pentraxins, where there is an abundance of both X-ray and cryoelectron microscopy (cryo-EM)-derived structures. This study presents a high-resolution structure of the prototypical long pentraxin, PTX3. Cryo-EM yielded a 2.5-Å map of the C-terminal pentraxin domains that revealed a radically different quaternary structure compared to other pentraxins, comprising a glycosylated D4 symmetrical octameric complex stabilized by an extensive disulfide network. The cryo-EM map indicated α-helices that extended N terminal of the pentraxin domains that were not fully resolved. AlphaFold was used to predict the remaining N-terminal structure of the octameric PTX3 complex, revealing two long tetrameric coiled coils with two hinge regions, which was validated using classification of cryo-EM two-dimensional averages. The resulting hybrid cryo-EM/AlphaFold structure allowed mapping of ligand binding sites, such as C1q and fibroblast growth factor-2, as well as rationalization of previous biochemical data. Given the relevance of PTX3 in conditions ranging from COVID-19 prognosis, cancer progression, and female infertility, this structure could be used to inform the understanding and rational design of therapies for these disorders and processes.

show abstract

“…ADCY1 and NPTX1 were also found to be associated with BD in our analysis as well as other GWAS studies 69,70 . ADCY1 plays a potential role in learning and memory 71,72 , whereas NPTX1 is required for neural cell speci cation and is also known to be involved in synaptic plasticity 73,74 .…”

Section: Discussionmentioning

confidence: 99%

Immunoglobulin genes expressed in lymphoblast cell lines discern and predict lithium response in bipolar disorder patients

Mizrahi

Choudhary

Ofer

et al. 2022

Preprint

View full text Add to dashboard Cite

Bipolar disorder (BD) is a neuropsychiatric mood disorder manifested by recurrent episodes of mania and depression. More than half of BD patients are non-responsive to lithium, the first-line treatment drug, complicating BD clinical management. Given its unknown etiology, it is pertinent to understand the genetic signatures that lead to variability in lithium treatment. We discovered a set of differentially expressed genes from the LCLs of 10 controls and 19 BD patients belonging mainly to the immunoglobulin gene family that can be used as potential biomarkers to diagnose and treat BD. Importantly, we trained a machine learning algorithm on our datasets that predicted the lithium response of BD subtypes with no errors, even when used on a different cohort of 24 BD patients acquired by a different laboratory. This proves the scalability of our methodology for predicting lithium response in BD and for a prompt and suitable decision on therapeutic interventions.

show abstract

Neuronal pentraxins as biomarkers of synaptic activity: from physiological functions to pathological changes in neurodegeneration

Cited by 51 publications

References 182 publications

Cerebrospinal FluidBiomarkers of Synaptic Dysfunction are Altered in Parkinson's Disease and Related Disorders

Cerebrospinal FluidBiomarkers of Synaptic Dysfunction are Altered in Parkinson's Disease and Related Disorders

PTX3 structure determination using a hybrid cryoelectron microscopy and AlphaFold approach offers insights into ligand binding and complement activation

Immunoglobulin genes expressed in lymphoblast cell lines discern and predict lithium response in bipolar disorder patients

Contact Info

Product

Resources

About