{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T20:53:01Z","timestamp":1761598381582,"version":"build-2065373602"},"reference-count":56,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T00:00:00Z","timestamp":1634688000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish Ministry of Science Innovation and Universities","award":["PID2019-110356RB- 259 I00\/ AEI \/ 10.13039\/501100011033"],"award-info":[{"award-number":["PID2019-110356RB- 259 I00\/ AEI \/ 10.13039\/501100011033"]}]},{"name":"Department of Economic and Business Development from Government of 260 Navarra","award":["0011-1411-2020-000028"],"award-info":[{"award-number":["0011-1411-2020-000028"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Olfactory dysfunction is considered an early prodromal marker of many neurodegenerative diseases. Neuropathological changes and aberrant protein aggregates occur in the olfactory bulb (OB), triggering a tangled cascade of molecular events that is not completely understood across neurological disorders. This study aims to analyze commonalities and differences in the olfactory protein homeostasis across neurological backgrounds with different spectrums of smell dysfunction. For that, an integrative analysis was performed using OB proteomics datasets derived from subjects with Alzheimer\u2019s disease (AD), Parkinson\u2019s disease (PD), mixed dementia (mixD), dementia with Lewy bodies (DLB), frontotemporal lobar degeneration (FTLD-TDP43), progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) with respect to OB proteome data from neurologically intact controls. A total of 80% of the differential expressed protein products were potentially disease-specific whereas the remaining 20% were commonly altered across two, three or four neurological phenotypes. A multi-level bioinformatic characterization revealed a subset of potential disease-specific transcription factors responsible for the downstream effects detected at the proteome level as well as specific densely connected protein complexes targeted by several neurological phenotypes. Interestingly, common or unique pathways and biofunctions were also identified, providing novel mechanistic clues about each neurological disease at olfactory level. The analysis of olfactory epithelium, olfactory tract and primary olfactory cortical proteotypes in a multi-disease format will functionally complement the OB dyshomeostasis, increasing our knowledge about the neurodegenerative process across the olfactory axis.<\/jats:p>","DOI":"10.3390\/ijms222111340","type":"journal-article","created":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T21:29:46Z","timestamp":1634765386000},"page":"11340","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Tackling the Biological Meaning of the Human Olfactory Bulb Dyshomeostatic Proteome across Neurological Disorders: An Integrative Bioinformatic Approach"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6182-7445","authenticated-orcid":false,"given":"Paz","family":"Cartas-Cejudo","sequence":"first","affiliation":[{"name":"Clinical Neuroproteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Navarra Institute for Health Research, Universidad P\u00fablica de Navarra (UPNA), IdiSNA, 3, 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mercedes","family":"Lach\u00e9n-Montes","sequence":"additional","affiliation":[{"name":"Clinical Neuroproteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Navarra Institute for Health Research, Universidad P\u00fablica de Navarra (UPNA), IdiSNA, 3, 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5072-4099","authenticated-orcid":false,"given":"Joaqu\u00edn","family":"Fern\u00e1ndez-Irigoyen","sequence":"additional","affiliation":[{"name":"Clinical Neuroproteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Navarra Institute for Health Research, Universidad P\u00fablica de Navarra (UPNA), IdiSNA, 3, 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8046-8102","authenticated-orcid":false,"given":"Enrique","family":"Santamar\u00eda","sequence":"additional","affiliation":[{"name":"Clinical Neuroproteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Navarra Institute for Health Research, Universidad P\u00fablica de Navarra (UPNA), IdiSNA, 3, 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,20]]},"reference":[{"key":"ref_1","first-page":"895","article-title":"Alzheimer\u2019s disease","volume":"461","author":"Mucke","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/nrn.2017.75","article-title":"Animal models of \u03b1-synucleinopathy for Parkinson disease drug development","volume":"18","author":"Koprich","year":"2017","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.nbd.2011.10.026","article-title":"Olfaction in Parkinson\u2019s disease and related disorders","volume":"46","author":"Doty","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1001\/jamaneurol.2015.2952","article-title":"Association Between Olfactory Dysfunction and Amnestic Mild Cognitive Impairment and Alzheimer Disease Dementia","volume":"73","author":"Roberts","year":"2016","journal-title":"JAMA Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/ana.21327","article-title":"The olfactory vector hypothesis of neurodegenerative disease: Is it viable?","volume":"63","author":"Doty","year":"2008","journal-title":"Ann. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/S1474-4422(17)30123-0","article-title":"Olfactory dysfunction in neurodegenerative diseases: Is there a common pathological substrate?","volume":"16","author":"Doty","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/0092-8674(94)90029-9","article-title":"Topographic organization of sensory projections to the olfactory bulb","volume":"79","author":"Vassar","year":"1994","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/S0092-8674(02)00713-4","article-title":"Anosmin-1, Defective in the X-Linked Form of Kallmann Syndrome, Promotes Axonal Branch Formation from Olfactory Bulb Output Neurons","volume":"109","author":"Julliard","year":"2002","journal-title":"Cell"},{"key":"ref_9","first-page":"52","article-title":"Wiring olfaction: The cellular and molecular mechanisms that guide the development of synaptic connections from the nose to the cortex","volume":"3","year":"2009","journal-title":"Front. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1016\/j.neurobiolaging.2007.08.001","article-title":"Reduced olfactory bulb and tract volume in early Alzheimer\u2019s disease\u2014A MRI study","volume":"30","author":"Thomann","year":"2009","journal-title":"Neurobiol. Aging"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s00401-011-0830-2","article-title":"Increased dopaminergic cells and protein aggregates in the olfactory bulb of patients with neurodegenerative disorders","volume":"122","author":"Caballero","year":"2011","journal-title":"Acta Neuropathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1007\/s00401-013-1144-3","article-title":"Reduced cholinergic olfactory centrifugal inputs in patients with neurodegenerative disorders and MPTP-treated monkeys","volume":"126","author":"Hernandez","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.neurobiolaging.2018.12.006","article-title":"Progressive signaling changes in the olfactory nerve of patients with Alzheimer\u2019s disease","volume":"76","author":"Bathini","year":"2019","journal-title":"Neurobiol. Aging"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1007\/s00401-014-1261-7","article-title":"Olfactory bulb involvement in neurodegenerative diseases","volume":"127","author":"Attems","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_15","first-page":"1","article-title":"Olfactory bulb neuroproteomics reveals a chronological perturbation of survival routes and a disruption of prohibitin complex during Alzheimer\u2019s disease progression","volume":"7","author":"Morales","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.neurobiolaging.2018.09.018","article-title":"Unveiling the olfactory proteostatic disarrangement in Parkinson\u2019s disease by proteome-wide profiling","volume":"73","author":"Iloro","year":"2019","journal-title":"Neurobiol. Aging"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.jprot.2019.04.011","article-title":"The olfactory bulb proteotype differs across frontotemporal dementia spectrum","volume":"201","author":"Schvartz","year":"2019","journal-title":"J. Proteom."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lach\u00e9n-Montes, M., \u00cd\u00f1igo-Marco, I., Cartas-Cejudo, P., Fern\u00e1ndez-Irigoyen, J., and Santamar\u00eda, E. (2021). Olfactory Bulb Proteomics Reveals Widespread Proteostatic Disturbances in Mixed Dementia and Guides for Potential Serum Biomarkers to Discriminate Alzheimer Disease and Mixed Dementia Phenotypes. J. Pers. Med., 11.","DOI":"10.20944\/preprints202104.0748.v1"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Lach\u00e9n-Montes, M., Mendizuri, N., Ausin, K., Andr\u00e9s-Benito, P., Ferrer, I., Fern\u00e1ndez-Irigoyen, J., and Santamar\u00eda, E. (2020). Amyotrophic Lateral Sclerosis Is Accompanied by Protein Derangements in the Olfactory Bulb-Tract Axis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218311"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Lach\u00e9n-Montes, M., Mendizuri, N., Schvartz, D., Fern\u00e1ndez-Irigoyen, J., S\u00e1nchez, J.C., and Santamar\u00eda, E. (2020). Proteomic Characterization of the Olfactory Molecular Imbalance in Dementia with Lewy Bodies. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176371"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1002\/prca.201500147","article-title":"Deconstructing the molecular architecture of olfactory areas using proteomics","volume":"10","author":"Santamaria","year":"2016","journal-title":"Proteom. - Clin. Appl."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1002\/prca.201400127","article-title":"Toward defining the anatomo-proteomic puzzle of the human brain: An integrative analysis","volume":"9","author":"Labarga","year":"2015","journal-title":"Proteom. - Clin. Appl."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.ymeth.2013.04.008","article-title":"Recent advances in quantitative neuroproteomics","volume":"61","author":"Craft","year":"2013","journal-title":"Methods"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1038\/nn.3829","article-title":"Decoding neuroproteomics: Integrating the genome, translatome and functional anatomy","volume":"17","author":"Kitchen","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_25","first-page":"1","article-title":"The human olfactory system in two proteinopathies: Alzheimer\u2019s and Parkinson\u2019s diseases","volume":"9","author":"Saiz","year":"2020","journal-title":"Transl. Neurodegener."},{"key":"ref_26","first-page":"1","article-title":"Astrogliosis and sexually dimorphic neurodegeneration and microgliosis in the olfactory bulb in Parkinson\u2019s disease","volume":"7","year":"2021","journal-title":"npj Park. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.nbd.2016.12.013","article-title":"The olfactory bulb as the entry site for prion-like propagation in neurodegenerative diseases","volume":"109","author":"Rey","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s40478-019-0713-7","article-title":"Neurodegeneration and contralateral \u03b1-synuclein induction after intracerebral \u03b1-synuclein injections in the anterior olfactory nucleus of a Parkinson\u2019s disease A53T mouse model","volume":"7","author":"Moriano","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.nbd.2012.04.001","article-title":"Cerebellar abnormalities in purine nucleoside phosphorylase deficient mice","volume":"47","author":"Mansouri","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_30","first-page":"89","article-title":"Dementia with Lewy Bodies: Molecular Pathology in the Frontal Cortex in Typical and Rapidly Progressive Forms","volume":"8","author":"Konetti","year":"2017","journal-title":"Front. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1111\/nan.12221","article-title":"Purine metabolism gene deregulation in Parkinson\u2019s disease","volume":"41","author":"Esparcia","year":"2015","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.neurobiolaging.2014.08.004","article-title":"Deregulation of purine metabolism in Alzheimer\u2019s disease","volume":"36","author":"Ansoleaga","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5830","DOI":"10.1523\/JNEUROSCI.17-15-05830.1997","article-title":"OCAM: A New Member of the Neural Cell Adhesion Molecule Family Related to Zone-to-Zone Projection of Olfactory and Vomeronasal Axons","volume":"17","author":"Yoshihara","year":"1997","journal-title":"J. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3420","DOI":"10.1523\/JNEUROSCI.3630-14.2015","article-title":"Ly6h Regulates Trafficking of Alpha7 Nicotinic Acetylcholine Receptors and Nicotine-Induced Potentiation of Glutamatergic Signaling","volume":"35","author":"Puddifoot","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.neuroscience.2011.03.057","article-title":"Collagen VI protects against neuronal apoptosis elicited by ultraviolet irradiation via an Akt\/Phosphatidylinositol 3-kinase signaling pathway","volume":"183","author":"Cheng","year":"2011","journal-title":"Neurosci."},{"key":"ref_36","first-page":"1","article-title":"The Roles of Peroxiredoxin 6 in Brain Diseases","volume":"2021","author":"Liao","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_37","first-page":"1","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/j.neuron.2008.01.027","article-title":"Role of IGF Signaling in Olfactory Sensory Map Formation and Axon Guidance","volume":"57","author":"Scolnick","year":"2008","journal-title":"Neuron"},{"key":"ref_39","first-page":"52","article-title":"IGF-I: A key growth factor that regulates neurogenesis and synaptogenesis from embryonic to adult stages of the brain","volume":"10","author":"Defterali","year":"2016","journal-title":"Front. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.neuron.2017.06.015","article-title":"IGF1-Dependent Synaptic Plasticity of Mitral Cells in Olfactory Memory during Social Learning","volume":"95","author":"Liu","year":"2017","journal-title":"Neuron"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1471-2105-4-2","article-title":"An automated method for finding molecular complexes in large protein interaction networks","volume":"4","author":"Bader","year":"2003","journal-title":"BMC Bioinform."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"11432","DOI":"10.1038\/srep11432","article-title":"TRRUST: A reference database of human transcriptional regulatory interactions","volume":"5","author":"Han","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3531","DOI":"10.1074\/jbc.M115.675488","article-title":"Regulation of Histone Acetylation by Autophagy in Parkinson Disease","volume":"291","author":"Park","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1186\/s12974-018-1286-2","article-title":"Targeting of the class II transactivator attenuates inflammation and neurodegeneration in an alpha-synuclein model of Parkinson\u2019s disease","volume":"15","author":"Williams","year":"2018","journal-title":"J. Neuroinflammation"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12920-020-00761-6","article-title":"Comparative transcriptome analysis of Parkinson\u2019s disease and Hutchinson-Gilford progeria syndrome reveals shared susceptible cellular network processes","volume":"13","author":"Hendrickx","year":"2020","journal-title":"BMC Med Genom."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"101446","DOI":"10.1016\/j.redox.2020.101446","article-title":"Distinct dual roles of p-Tyr42 RhoA GTPase in tau phosphorylation and ATP citrate lyase activation upon different A\u03b2 concentrations","volume":"32","author":"Cap","year":"2020","journal-title":"Redox Biol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Lopez-Lee, C., Kodama, L., and Gan, L. (2021). Sex Differences in Neurodegeneration: The Role of the Immune System in Humans. Biol. Psychiatry.","DOI":"10.1016\/j.biopsych.2021.01.002"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1126\/science.6505700","article-title":"Smell Identification Ability: Changes with Age","volume":"226","author":"Doty","year":"1984","journal-title":"Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"69663","DOI":"10.18632\/oncotarget.18193","article-title":"Progressive modulation of the human olfactory bulb transcriptome during Alzheimer\u00b4s disease evolution: Novel insights into the olfactory signaling across proteinopathies","volume":"8","author":"Zelaya","year":"2017","journal-title":"Oncotarget"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"14271","DOI":"10.1038\/ncomms14271","article-title":"Accelerating the search for the missing proteins in the human proteome","volume":"8","author":"Baker","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4117","DOI":"10.1021\/acs.jproteome.8b00494","article-title":"In Silico Peptide Repertoire of Human Olfactory Receptor Proteomes on High-Stringency Mass Spectrometry","volume":"18","author":"Adhikari","year":"2019","journal-title":"J. Proteome Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) Hallmark Gene Set Collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"D613","DOI":"10.1093\/nar\/gkaa1024","article-title":"WikiPathways: Connecting communities","volume":"49","author":"Martens","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"D649","DOI":"10.1093\/nar\/gkx1132","article-title":"The Reactome Pathway Knowledgebase","volume":"46","author":"Fabregat","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"D353","DOI":"10.1093\/nar\/gkw1092","article-title":"KEGG: New perspectives on genomes, pathways, diseases and drugs","volume":"45","author":"Kanehisa","year":"2017","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11340\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:19:26Z","timestamp":1760167166000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11340"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,20]]},"references-count":56,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222111340"],"URL":"https:\/\/doi.org\/10.3390\/ijms222111340","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2021,10,20]]}}}