{"database":"Pride","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Xlsx":["ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD037113/Experimental_design.xlsx","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD037113/Report.xlsx"],"Other":["ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD037113/20200917_TIMS1_nLC14_NHS_FLQ_120min_010-001-15_B3_1_1998.d.zip","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD037113/20200917_TIMS1_nLC14_NHS_FLQ_120min_010-001-06_A6_1_1984.d.zip","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD037113/20200917_TIMS1_nLC14_NHS_FLQ_120min_010-001-19_B7_1_1999.d.zip","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD037113/20200917_TIMS1_nLC14_NHS_FLQ_120min_010-001-05_A5_1_1981.d.zip","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD037113/20200917_TIMS1_nLC14_NHS_FLQ_120min_010-001-14_B2_1_1995.d.zip","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD037113/20200917_TIMS1_nLC14_NHS_FLQ_120min_010-001-01_A1_1_1980.d.zip","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD037113/20200917_TIMS1_nLC14_NHS_FLQ_120min_010-001-03_A3_1_1986.d.zip","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD037113/20200917_TIMS1_nLC14_NHS_FLQ_120min_010-001-16_B4_1_2001.d.zip","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD037113/20200917_TIMS1_nLC14_NHS_FLQ_120min_010-001-04_A4_1_1989.d.zip","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD037113/20200917_TIMS1_nLC14_NHS_FLQ_120min_010-001-02_A2_1_1983.d.zip","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD037113/20200917_TIMS1_nLC14_NHS_FLQ_120min_010-001-18_B6_1_1996.d.zip","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD037113/20200917_TIMS1_nLC14_NHS_FLQ_120min_010-001-08_A8_1_1990.d.zip","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD037113/20200917_TIMS1_nLC14_NHS_FLQ_120min_010-001-13_B1_1_1992.d.zip","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD037113/20200917_TIMS1_nLC14_NHS_FLQ_120min_010-001-20_B8_1_2002.d.zip","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD037113/20200917_TIMS1_nLC14_NHS_FLQ_120min_010-001-17_B5_1_1993.d.zip","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD037113/20200917_TIMS1_nLC14_NHS_FLQ_120min_010-001-07_A7_1_1987.d.zip"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"labhead_mail":["niels.skotte@sund.ku.dk"],"submitter":["Niels Henning Skotte"],"technology_type":["Mass Spectrometry","Shotgun proteomics"],"disease":["Parkinson's Disease"],"software":[""],"submitter_keywords":["Snrna-seq","Lc-ms/ms","Glutamatergic neurotransmission","Ifnar1","Parkinson’s disease dementia"],"full_dataset_link":["https://www.ebi.ac.uk/pride/archive/projects/PXD037113"],"tissue":["Brain"],"sample_protocol":["Sample preparation for mass spectrometry Snap-frozen cortex and hippocampus tissues were lysed in SDC alkylation and reduction lysis buffer (1% (w/v) sodium deoxycholate, 100 mM Tris pH 8, 40 mM CAA, 10 mM TCEP) using mechanical homogenizer (IKA® ULTRA-TURRAX® disperser, Merck) for 20 s. Lysates were boiled at 95°C for 10 min with continuous vortexing at 1200 rpm on a thermomixer (Eppendorf) to denature proteins. Samples were then sonicated using the Covaris Adaptive Focused Acoustics (AFA) sonication system (450W power, 50% duty factor, 200 cycles per burst) (Covaris, USA).  Protein concentrations were measured using BCA assay (ThermoFisher Scientific). Proteins were digested overnight using trypsin (1:100 w/w, Sigma-Aldrich) and LysC (1/100 w/w, Wako) at 37°C. The next day fresh enzyme was added for another 2 h. The peptides were acidified by 1% trifluoroacetic acid (TFA) (Merck) to quench digestion. Peptide concentration was estimated using Nanodrop and peptide mixture was purified by solid phase extraction in Stage-Tips (SDB-RPS material, two 14-gauge plugs) for desalting and concentration. Peptides were washed twice with isopropanol/1% TFA and subsequently twice with 0.2% TFA, then eluted with 80% acetonitrile/1% ammonia. Eluted samples were reduced by vacuum centrifugation at 60°C and peptide concentration was determined by Nanodrop (ThermoFisher Scientific) measurement at A280 nm. Sample concentrations were adjusted to 200 ng per injection in buffer A* (5% ACN / 0.1% TFA) for LC-MS/MS analysis.  LC-MS/MS Analysis Samples were analyzed with nanoflow Easy-nLC 1200 (Thermo Fisher Scientific, Denmark) connected to a trapped ion mobility spectrometry quadrupole time-of-flight mass spectrometer (TimsTOF Pro, Bruker Daltonik GmbH, Germany) with a nano-electrospray ion source (Captive spray, Bruker Daltonik GmbH). Peptides were separated on a 50 cm in-house packed column (75 μm inner diameter × 50 cm length) with 1.9 μm ReproSilPur C18-AQ silica beads (Dr. Maisch, Germany). Column temperature was kept at 60°C using an in-house made column oven. Peptide separation was achieved by 120 min gradients. Peptides were loaded and eluted with a nonlinear gradient of increasing buffer B (0.1% formic acid and 80% acetonitrile) and decreasing buffer A (0.1% formic acid) at a flow rate of 300 nl/min. Buffer B was increased slowly from 5% to 30% over 95 min and ramped to 60% over 5 min, and then to 95% over 5 min, where it was held for 5 min before being drop down to 5% again for column re-equilibration for 5 min. Sample acquisition was randomized to avoid bias. Mass spectrometric analysis was performed as described in Brunner et al.36, either in data-dependent (ddaPASEF) or data-independent (diaPASEF) mode. We used the ddaPASEF method for library generation. For ddaPASEF, 1 MS1 survey TIMS-MS and 10 PASEF MS/MS scans were acquired per acquisition cycle. Ion accumulation and ramp time in the dual TIMS analyzer was set to 100 ms each and we analyzed the ion mobility range from 1/K0 = 1.6 Vs cm-2 to 0.6 Vs cm-2. Precursor ions for MS/MS analysis were isolated with a 2 Th window for m/z < 700 and 3 Th for m/z >700 in a total m/z range of 100-1.700 by synchronizing quadrupole switching events with the precursor elution profile from the TIMS device. Collision energy was lowered linearly as a function of increasing mobility starting from 59 eV at 1/K0 = 1.6 VS cm-2 to 20 eV at 1/K0 = 0.6 Vs cm-2. Singly charged precursor ions were excluded with a polygon filter (Bruker Daltonik GmbH). Precursors for MS/MS were picked at an intensity threshold of 1.000 AU and re-sequenced until reaching a ‘target value’ of 20.000 AU taking into account a dynamic exclusion of 40 s elution. For diaPASEF analysis, we made use of the correlation of Ion Mobility (IM) with m/z and synchronized the elution of precursors from each IM scan with the quadrupole isolation window. The collision energy was ramped linearly as a function of the IM from 59 eV at 1/K0 = 1.6 Vs cm−2 to 20 eV at 1/K0 = 0.6 Vs cm−2."],"repository":["Pride"],"quantification_method":[""],"modification":[""],"data_protocol":["Spectronaut Data Processing Data analysis of mass spectrometric raw files acquired in ddaPASEF mode were analyzed with Spectronaut Pulsar (version 2.4, Biognosys AG, Schlieren, Switzerland) to generate the library using the default settings. The library consisted of 175,301 precursors, 115,684 peptides, 10,191 protein groups. The ddaPASEF library were used in the targeted analysis of diaPASEF data for the CNS data against the Mus musculus UniProt fasta database (2019 release, UP00000589_10090). Peptide spectral match (PSM) and protein level FDR of 1%. A minimum of seven amino acids was required including N-terminal acetylation and methionine oxidation as variable modifications and carbamidomethylation as a fixed modification. Enzyme specificity was set to trypsin/P with a maximum of two allowed missed cleavages. Peptide identifications by MS/MS were transferred by matching four-dimensional isotope patterns between the runs (MBR) with a 0.7 min retention time match window and a 0.05 1/K0 ion mobility window. diaPASEF analysis was conducted with the Spectronaut software (v14.8, Biognosys AG, Schlieren, Switzerland) under default settings. Search parameters were according to default settings. ‘Cross run normalization’ was enabled with strategy of ‘local normalization’ based on rows with ‘Qvalue complete’. FDR was set to 1% at peptide precursor level and 1% at protein level. Decoy hits and proteins, which did not pass the Q-value threshold, were filtered out prior to data analysis.  MS Data Analysis and Visualization Quantitative protein abundance data generated in Spectronaut was analyzed in a Python-based version of the Clinical Knowledge Graph (CKG) (v1.0b1 BETA, https://CKG.readthedocs.io)37, where data handling including filtering, normalization, annotation, statistics, enrichment analysis, and visualization were conducted. We filtered for at least 3 quantified values out 4 replicates in at least one group when analyzing the data. Missing values were imputed using a mixed model of k-Nearest Neighbor’s imputation method (KNN) which assumes that the values are Missing Completely At Random (MCAR), and Probabilistic Minimum Imputation approach (MinProb) for missing values that are considered Missing Not At Random (MNAR) (downshift of 2.4 standard deviations and a width of 0.3 standard deviations). Protein intensities were log2-transformed for further analysis. For the two-samples t-tests, we analyzed each region separately to eliminate noise from imputation and to achieve high stringency and confidence. For generation of the abundance distribution curves, median protein abundances across all samples within a proteome were used. Coefficients of variation (CVs) were calculated and reported as overall coefficient of variation. Correlations between LFQ intensities within biological replicates and regions were done by Pearson correlations. The subsequent data analysis includes a dimensionality reduction step to enable visualization of the high dimensional proteomic datasets using two or three-dimensional representations. We implemented linear dimensionality reduction (Principal Component Analysis (PCA)). Statistical tests across 4 groups (2 genotypes and 2 regions) were performed by a one-way ANOVA using Benjamini-Hochberg False Discovery Rate (BH-FDR) to correct for multiple hypothesis testing. All t-tests performed were two-sided, unpaired, and corrected for multiple testing. Volcano plots were generated using FDR < 0.05."],"omics_type":["Proteomics"],"labhead":["Niels Henning Skotte"],"instrument_platform":[""],"labhead_affiliation":["Skotte Research Group  Department for Drug Design and Pharmacology Molecular Neuroprotection  Novo Nordisk Foundation Center for Protein Research Clinical Proteomics  University of Copenhagen"],"submission_type":["PARTIAL"],"species":["Mus Musculus (mouse)"],"submitter_mail":["niels.skotte@sund.ku.dk"],"publication":["42226039 Villanueva EB, Zebec Z, Cisquella-Serra M, Lundstrøm J, Andersen JV, Qvist FL, Westi EW, Marin A, Jimenez-Duran G, Riera-Ponsati L, Tresse E, Kretz O, Loreth D, Goldmann T, Blank T, Prinz M, Aldana BI, Mann M, Skotte NH, Issazadeh-Navikas S. Distinct and combined interferon-ɑ/β-receptor-1 loss in neurons and astrocytes disrupt brain energy metabolism and drive Parkinsonian dementia. J Biomed Sci. 2026 33(1):57 10.1186/s12929-026-01257-8"],"submitter_affiliation":["University of Copenhagen"],"submitter_country":["Denmark"],"pubmed_abstract":["<h4>Background</h4>Dysregulated interferon-alpha/beta-receptor 1 (IFNAR1) signaling was recently identified to contribute to the development of sporadic Parkinson's disease (PD) into PD with Dementia (PDD). The molecular, cellular, and phenotypic impacts of brain IFNAR1 loss in aging have not been explored in vivo, which may reveal novel disease mechanisms and therapeutic targets.<h4>Methods</h4>Single nuclei RNA sequencing (snRNA-seq), liquid chromatography tandem mass spectrometry (LC-MS/MS), functional metabolic mapping, flow cytometry, quantitative PCR (qPCR), in situ hybridization, immunofluorescence and immunohistochemistry, Western blotting, and behavior analyses were used to investigate the molecular, cellular, and phenotypic impacts of IFNAR1 loss in vivo.<h4>Results</h4>Baseline IFNAR1 expression varies among major brain cell types, including neurons and astrocytes, and is differentially affected in PD and Lewy Body Dementia patients compared to unaffected controls. Neuron- and astrocyte-specific transcriptomic and proteomic alterations in Ifnar1<sup>-/-</sup> mice implicate mitochondrial defects, defective mitophagy, and synergistic dysfunctional neurotransmission upon IFNAR1 loss, leading to glucose hypermetabolism measured by functional metabolic analysis. Consequently, Ifnar1<sup>-/-</sup> mice exhibited PDD-like pathogenesis, including dopaminergic cell loss in the substantia nigra, cortical neurodegeneration, Lewy-body-like inclusions, neuroinflammation, and progressive PDD-like behavior deficits. Brain cell-specific IFNAR1 loss examined in vivo revealed delayed but distinct development of PDD-like phenotypes, where neuropathology, motor, and cognitive behavior deficits were recapitulated only in mice lacking neuronal IFNAR1, and behavior resembling neuropsychiatric abnormalities recapitulated only in mice lacking astrocytic IFNAR1.<h4>Conclusions</h4>IFNAR1 plays a crucial role in brain and mitochondrial homeostasis, loss of which results in neurodegeneration and neuropathology resembling PDD. Differential neuropathology and behavioral outcomes upon neuronal vs astrocytic IFNAR1 loss emphasizes a need for understanding neurodegenerative pathophysiology in cell-specific contexts. Trial registration Not applicable as the study does not include a clinical trial."],"pubmed_title":["Distinct and combined interferon-ɑ/β-receptor-1 loss in neurons and astrocytes disrupt brain energy metabolism and drive Parkinsonian dementia."],"pubmed_authors":["Villanueva Erika B EB, Zebec Zala Z, Cisquella-Serra Marina M, Lundstrøm Jon J, Andersen Jens V JV, Qvist Filippa L FL, Westi Emil W EW, Marin Andrea A, Jimenez-Duran Gisela G, Riera-Ponsati Lluís L, Tresse Emilie E, Kretz Oliver O, Loreth Desiree D, Goldmann Tobias T, Blank Thomas T, Prinz Marco M, Aldana Blanca I BI, Mann Matthias M, Skotte Niels H NH, Issazadeh-Navikas Shohreh S"],"additional_accession":[]},"is_claimable":false,"name":"Distinct Impact of Neuronal and Astrocytic IFNAR1 Loss in Parkinson-like Dementia","description":"Interferon-alpha/beta-receptor (IFNAR) signal defects were recently identified to contribute to sporadic Parkinson’s disease (PD) with dementia (PDD). Mice lacking interferon-beta (IFNβ) develop PDD-like disease; however, the phenotypic, cellular, and molecular impacts of IFNAR1 loss in vivo have not been explored. Studying cell-specific pathology in Ifnar1–/– mice may reveal potential disease-modifying therapeutic targets for PDD. Here, we present that Ifnar1–/– mice exhibit PDD-like pathogenesis, including dopaminergic neurodegeneration in the substantia nigra, Lewy-body-like alpha-synuclein+ inclusions, gliosis-associated phosphorylated-tau and amyloid-beta proteinopathy, and progressive PDD-like behavior deficits. Hallmark neuropathology and motor and cognitive behavior deficits were specifically recapitulated in mice lacking neuronal IFNAR1. Ifnar1–/– mice also exhibited early-onset nociceptive pain and neuropsychiatric abnormalities, recapitulated in mice lacking astrocytic IFNAR1. Neuron/astrocyte-specific transcriptomic and proteomic alterations in early-manifest Ifnar1–/– mice implicate synergistic dysfunctional excitatory neurotransmission upon IFNAR1 loss, leading to glucose hypermetabolism prior to cognitive decline. Targeted restoration of dysfunctional neuronal and astrocytic IFNAR1 could therefore potentially mitigate PDD progression through concerted regulation of excitatory neurotransmission.","dates":{"publication":"2026-06-08","submission":"2022-09-30"},"accession":"PXD037113","cross_references":{"TAXONOMY":["NEWT:330879","NEWT:108018","NEWT:377960","NEWT:1131","NEWT:35795","NEWT:2042546","NEWT:259447","NEWT:295546","NCBITaxon:2719036","NEWT:1334565","NEWT:625351","NEWT:258594","NCBITaxon:1280","NEWT:1126","NEWT:112503","NEWT:1129","NEWT:309807","NEWT:59753","NEWT:89184","NEWT:309800","NEWT:281395","NEWT:247480","NEWT:1211601","NEWT:876138","NEWT:44271","NEWT:193516","NEWT:2315688","NEWT:1367493","NEWT:592321","NEWT:1073882","NEWT:6819","NEWT:46429","NEWT:475174","NEWT:1599","NEWT:428386","NEWT:1117","NEWT:498257","NEWT:10036","NEWT:32264","NEWT:12215","NEWT:1590","NEWT:10034","NEWT:33114","NEWT:1596","NEWT:2736291","NEWT:661410","NEWT:638632","NEWT:224326","NEWT:294671","NEWT:376619","NEWT:1748418","NCBITaxon:79857","NEWT:1096976","NEWT:3765","NEWT:3767","NEWT:1589","NEWT:135622","NEWT:4615","NEWT:672127","NEWT:35786","NEWT:1580","NEWT:399784","NEWT:96731","NEWT:656061","NEWT:37965","NEWT:656064","NEWT:1582","NEWT:3760","NEWT:1584","NEWT:2086595","NEWT:36630","NEWT:1585","NEWT:383379","NEWT:381198","NEWT:418106","NCBITaxon:12721","NEWT:166340","NEWT:10029","NEWT:913645","NEWT:2492962","NEWT:641809","NEWT:44250","NEWT:1392488","NEWT:38815","NEWT:317447","NEWT:4688","NEWT:3357","NEWT:7719","NEWT:29073","NEWT:5530","NEWT:868565","NEWT:135674","NEWT:1562698","NEWT:79329","NEWT:30069","NEWT:12637","NEWT:59729","NEWT:2164133","NEWT:295105","NEWT:2767846","NEWT:108061","NEWT:60711","NEWT:2020713","NEWT:224308","NEWT:3347","NEWT:49928","NEWT:3349","NEWT:160621","NEWT:2502409","NEWT:212790","NEWT:110368","NEWT:55350","NEWT:1916073","NEWT:1310161","NEWT:1230383","NEWT:77133","NEWT:145481","NEWT:1310165","NEWT:29058","NCBITaxon:79824","NEWT:468822","NEWT:410658","NEWT:5516","NEWT:44688","NEWT:44689","NEWT:370038","NEWT:498211","NEWT:345076","NEWT:347256","NEWT:5518","NEWT:398007","NEWT:1527468","NEWT:498217","NEWT:498216","NEWT:11320","NEWT:246196","NEWT:246197","NEWT:145458","NEWT:1310173","NEWT:200795","NEWT:342808","NEWT:2579791","NEWT:44685","NEWT:161934","NEWT:156587","NEWT:1148","NEWT:5508","NEWT:3329","NEWT:419481","NEWT:5507","NEWT:260499","NEWT:410661","NEWT:329854","NEWT:1140","NCBITaxon:2157","NEWT:2066563","NEWT:2649329","NEWT:1143","NEWT:99802","NEWT:1287689","NEWT:1094343","NEWT:1462472","NEWT:1336795","NEWT:644042","NEWT:150808","NEWT:709964","NEWT:1182590","NEWT:3712","NEWT:3711","NEWT:156974","NEWT:3714","NCBITaxon:37162","NEWT:270643","NEWT:3715","NEWT:1538","NEWT:2065263","NEWT:199225","NEWT:1549675","NEWT:177437","NEWT:717966","NEWT:9014","NEWT:10891","NEWT:10418","NEWT:118698","NEWT:1616117","NEWT:118696","NEWT:34865","NEWT:52283","NEWT:28174","NEWT:284812","NEWT:8175","NEWT:43330","NEWT:1603293","NEWT:29022","NEWT:44664","NEWT:43346","NEWT:3702","NEWT:1245466","NEWT:3704","NEWT:244366","NEWT:96795","NEWT:1246791","NEWT:176597","NEWT:118694","NEWT:2850","NEWT:118691","NEWT:9005","NEWT:34871","NEWT:9006","NEWT:33548","NEWT:52299","NEWT:1883426","NEWT:8165","NEWT:96794","NEWT:10401","NEWT:10886","NEWT:3708","NEWT:332648","NEWT:44670","NEWT:926571","NEWT:536231","NEWT:376219","NEWT:219813","NEWT:1510","NEWT:1955249","NEWT:215451","NEWT:460519","NEWT:1515","NEWT:572307","NEWT:1432138","NEWT:2714896","NEWT:1424507","NEWT:1194599","NEWT:272844","NEWT:1348799","NEWT:1608994","NEWT:33995","NEWT:55784","NEWT:1303443","NEWT:9483","NEWT:485","NEWT:329032","NEWT:56636","NEWT:2499525","NEWT:55307","NEWT:1122981","NEWT:2853422","NEWT:1122984","NEWT:487","NEWT:1538553","NEWT:1679718","NEWT:480","NEWT:67767","NEWT:45972","NEWT:2830","NEWT:46835","NEWT:109757","NEWT:582580","NEWT:1185650","NEWT:216778","NEWT:1502","NEWT:128017","NEWT:2836","NEWT:376686","NEWT:237610","NEWT:95486","EFO:0001352","NEWT:219809","NEWT:219808","NEWT:119562","NEWT:1883446","NEWT:31345","NEWT:1233435","NEWT:118223","NEWT:11757","NEWT:141469","NEWT:987059","NEWT:109760","NEWT:29031","NEWT:317047","NEWT:1509","NEWT:491","NEWT:460523","NEWT:45954","NEWT:1578","NEWT:235443","NEWT:1579","NEWT:1757312","NEWT:85694","NEWT:109786","NEWT:1922344","NEWT:108458","NEWT:5936","NEWT:85692","NEWT:321967","NEWT:320637","NEWT:1078283","NEWT:3750","NEWT:983964","NEWT:11706","NEWT:32644","NEWT:527796","NEWT:279010","NEWT:291146","NEWT:499175","NEWT:109779","NEWT:3745","NEWT:1715989","NCBITaxon:4751","NEWT:3747","NEWT:278161","NEWT:1116234","NEWT:415978","NEWT:235455","NEWT:1255228","NEWT:410289","NEWT:191701","NEWT:373153","NEWT:1640278","NEWT:9054","NEWT:1092586","NEWT:472","NEWT:940825","NEWT:29459","NEWT:529507","NEWT:1071661","NEWT:1380096","NEWT:28128","NEWT:470","NEWT:41122","NEWT:5911","NEWT:1328300","NEWT:748693","NCBITaxon:50557","NEWT:39251","NEWT:29491","NEWT:911022","NEWT:101841","NEWT:446","NEWT:153481","NEWT:2014887","NEWT:717989","NEWT:33952","NEWT:1255232","NEWT:11723","NEWT:445","NEWT:153009","NEWT:1004879","NEWT:261756","NEWT:166314","NEWT:166313","NEWT:63366","NEWT:63367","NEWT:29488","NEWT:1871049","NEWT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