A biomarker-authenticated model of schizophrenia implicating NPTX2 loss of function

Xiao, Mei-Fang; Roh, Seung-Eon; Zhou, Jiechao; Chien, Chun-Che; Lucey, Brendan P.; Craig, Michael T.; Hayes, Lindsay N.; Coughlin, Jennifer M.; Leweke, F. Markus; Jia, Min; Xu, Desheng; Zhou, Weiqiang; Talbot, C. Conover; Arnold, Don W.; Staley, M.; Jiang, Cindy; Reti, Irving M.; Sawa, Akira; Pelkey, Kenneth A.; McBain, Chris J.; Savonenko, Alena; Worley, Paul F.

doi:10.1126/sciadv.abf6935

Cited by 26 publications

(27 citation statements)

References 64 publications

(117 reference statements)

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“…Nptx2 KO mice parallel the phenotype of C4-overexpressing mice; we found elevated levels of cleaved C4b in brains from Nptx2 KO mice and we previously reported that Nptx2 KO mice exhibit increased vulnerability to social isolation stress with emergent neuropsychiatric behavioral deficits (Xiao et al, 2021). The present finding extends the notion that Nptx2 loss of function spans the complex genetics of schizophrenia as a shared common pathway (Xiao et al, 2021).…”

Section: Discussionsupporting

confidence: 85%

“…In AD, Nptx2 is decreased in postmortem brain and in patient CSF where its levels correlate with disease status, cognitive performance and disease progression (Xiao et al, 2017). Nptx2 levels are also reduced in CSF from schizophrenia patients, and Nptx2 knockout (Nptx2 KO ) mice show schizophrenia-related behavioral deficits (Xiao et al, 2021). Given the identification of Nptx2 as a regulator of complement, we next examined if Nptx2 KO mouse brains exhibited dysregulated complement.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, Nptxr-containing complexes can be shed from the synapse upon enzymatic cleavage of Nptxr (Cho et al, 2008). In vivo imaging of Nptx2 indicates that the Nptx1/2/r complex is exocytosed at excitatory synapses on parvalbumin interneurons (PV-IN) during periods of behavioral activity and as much as 40% is later shed on a diurnal and circadian schedule during sleep, presumably in the process of circuit refinement (Xiao et al, 2021). The shedding process can be monitored in human subjects by measuring NPTX2 in CSF and is disrupted by sleep deprivation in both mouse and human subjects highlighting its dynamic physiological regulation (Xiao et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…In an AD amyloidosis mouse model, Nptx2 amplifies the effect of amyloid-beta (Aß) to reduce inhibitory circuit function required for gamma rhythmicity (Xiao et al, 2017). Nptx2 in CSF serves as a biomarker in genetic FTD (Ende et al, 2020), AD (Galasko et al, 2019;Xiao et al, 2017), Down syndrome (Belbin et al, 2020), Dementia with Lewy Bodies (Steenoven et al, 2020), schizophrenia (Xiao et al, 2021) and normal aging (Soldan et al, 2019), and consistently correlates with cognitive measures. The reduction of Nptx2 in CSF may reflect inhibitory circuit dysfunction with associated excitatory synapse damage or loss, a pathomechanism common between neurodegenerative and neuropsychiatric diseases (Styr and Slutsky, 2018;Xiao et al, 2017Xiao et al, , 2021.…”

Section: Introductionmentioning

confidence: 99%

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Neuronal pentraxin Nptx2 regulates complement activity in the brain

Zhou

Wade

Graykowski

et al. 2022

Preprint

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Complement overactivation mediates microglial synapse elimination in neurological diseases like Alzheimer disease and frontotemporal dementia (FTD), but how complement activity is regulated in the brain remains largely unknown. We identified that the secreted neuronal pentraxin Nptx2 binds complement C1q and thereby regulates its activity in the brain. Nptx2-deficient mice show increased complement activity and C1q-dependent microglial synapse engulfment and loss of excitatory synapses. In a neuroinflammation culture model and in aged TauP301S mice, AAV-mediated neuronal overexpression of Nptx2 was sufficient to restrain complement activity and ameliorate microglia-mediated synapse loss. Analysis of human CSF samples from a genetic FTD cohort revealed significantly reduced levels of Nptx2 and Nptx2-C1q protein complexes in symptomatic patients, which correlated with elevated C1q and activated C3. Together, these results show that Nptx2 regulates complement activity and microglial synapse elimination in the healthy and diseased brain and that diminished Nptx2 levels might exacerbate complement-mediated neurodegeneration in FTD patients.

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Section: Discussionsupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neuronal pentraxin Nptx2 regulates complement activity in the brain

Zhou

Wade

Graykowski

et al. 2022

Preprint

Self Cite

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“…EGR2 [99], ADCYAP1 [100], CHRNA7 [101], NRN1 [102], ETV5 [103], STXBP1 [104], CAMKK2 [105], VAMP2 [106], SYNGR1 [107], NOD2 [108], TLR2 [109], BRCA2 [110] and LEF1 [111] were previously reported to be critical for the development of bipolar disorder. Accumulating evidence shows that EGR2 [112], WNT1 [113], ARC (activity regulated cytoskeleton associated protein) [114], ADCYAP1 [115], SCN5A [116], RTN4R [117], CHRNA7 [118], NRGN (neurogranin) [119], CHRM1 [120], CCK (cholecystokinin) [121], RGS4 [122], LINGO1 [123], PAK1 [124], PCDH19 [125], NRN1 [126], CX3CL1 [127], CNTNAP2 [128], SLC12A5 [129], GAS7 [130], NTNG1 [131], RAB3A [132], STXBP1 [104], CHRNB2 [133], CDK5 [134], HTR5A [135], SLC30A3 [136], HTR3B [137], HTR2C [138], TAMALIN (trafficking regulator and scaffold protein tamalin) [139], STX1A [140], GRM2 [141], SLC1A6 [142], NPTX2 [143], CAMKK2 [144], SYP (synaptophysin) [145], VAMP2 [146], ATP1A3 [147], SV2A [148], CNTNAP2 [149], CAP2[150], SYNGR1 [151], SNCB (synuclein beta) [152], RBP4 [153], KIF17 [154], CHI3L1 [155], CCR5 [156], C1QB [157], TLR7 [158], TLR2 [159], MNDA (myeloid cell nuclear differentiation antigen) [160], C3 [161], IL2RG [162], MICB (MHC class I polypeptide-related sequence B) [163], FKBP5 [164], NEFH (neurofilament heavy chain) [165], CELSR1 [166], APBB1IP [167], CD34 [168], BRCA2 [110], ITGB3 […”

Section: Discussionmentioning

confidence: 99%

Bioinformatics and next generation sequencing data analysis to identify key genes and pathways influencing in Parkinson’s disease

Vastrad¹,

Vastrad²

2022

Preprint

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Parkinson's disease (PD) is the most commonly diagnosed neurodegenerative disorder Identification of novel prognostic and pathogenesis biomarkers plays a pivotal role in the management of the PD. Next generation sequencing (NGS) dataset from the GEO (Gene Expression Omnibus) database were used to identify differentially expressed genes (DEGs) in PD. Gene Ontology (GO) and REACTOME pathway enrichmental analyses were performed to elucidate the functional roles of the DEGs. Protein-protein interaction (PPI), modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network were established. The receiver operating characteristic curve (ROC) analysis was used to explore the diagnostic values of hub genes in PD. In total, 957 DEGs were identified, of which 478 were up regulated genes and 479 were down regulated genes. GO and pathway enrichment analysis results revealed that the up regulated genes were mainly enriched in nervous system development, cell junction, transporter activity and neuronal system, whereas down regulated genes were mainly enriched in response to stimulus, cell periphery, identical protein binding and immune system. The top hub genes in the constructed PPI network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network were OTUB1, PPP2R1A, AP2M1, PIN1, USP11, CDK2, IQGAP1, NEDD4, VIM and CDK1. Furthermore, ROC analysis showed that hub genes were having good diagnostic values. We identified a series of essential genes along with the pathways that were most closely related with PD initiation and progression. Our results provide a more detailed molecular mechanism for the advancement of PD, shedding light on the potential biomarkers and therapeutic targets.

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NPTX2 in Cerebrospinal Fluid Predicts the Progression From Normal Cognition to Mild Cognitive Impairment

Soldan

Ryu

et al. 2023

Annals of Neurology

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ObjectiveThis study examined whether cerebrospinal fluid (CSF) baseline levels of the synaptic protein NPTX2 predict time to onset of symptoms of mild cognitive impairment (MCI), both alone and when accounting for traditional CSF Alzheimer's disease (AD) biomarker levels. Longitudinal NPTX2 levels were also examined.MethodsCSF was collected longitudinally from 269 cognitively normal BIOCARD Study participants (mean baseline age = 57.7 years; mean follow‐up = 16.3 years; n = 77 progressed to MCI/dementia). NPTX2 levels were measured from 3 correlated peptides using quantitative parallel reaction monitoring mass spectrometry. Levels of Aβ42/Aβ40, p‐tau181, and t‐tau were measured from the same CSF specimens using Lumipulse automated electrochemiluminescence assays.ResultsIn Cox regression models, lower baseline NPTX2 levels were associated with an earlier time to MCI symptom onset (hazard ratio [HR] = 0.76, SE = 0.09, p = 0.023). This association was significant for progression within 7 years (p = 0.036) and after 7 years from baseline (p = 0.001). Baseline NPTX2 levels improved prediction of time to MCI symptom onset after accounting for baseline AD biomarker levels (p < 0.01), and NPTX2 did not interact with the CSF AD biomarkers or APOE‐ε4 genetic status. In linear mixed effects models, higher baseline p‐tau181 and t‐tau levels were associated with higher baseline levels of NPTX2 (both p < 0.001) and greater rates of NPTX2 declines over time.InterpretationNPTX2 may be a valuable prognostic biomarker during preclinical AD that provides additive and independent prediction of MCI onset among individuals who are cognitively normal. We hypothesize that NPTX2‐mediated circuit homeostasis confers resilience during the early phase of AD. ANN NEUROL 2023

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A biomarker-authenticated model of schizophrenia implicating NPTX2 loss of function

Abstract: CSF NPTX2 is a biomarker of schizophrenia and supports a model that integrates across genetics, pharmacology, and behavior.

Cited by 26 publications

References 64 publications

Neuronal pentraxin Nptx2 regulates complement activity in the brain

Neuronal pentraxin Nptx2 regulates complement activity in the brain

Bioinformatics and next generation sequencing data analysis to identify key genes and pathways influencing in Parkinson’s disease

NPTX2 in Cerebrospinal Fluid Predicts the Progression From Normal Cognition to Mild Cognitive Impairment

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