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Although their signalling pathways are not fully understood, the chitinases are considered active immunomodulators across several cell types. Specific isoforms, including chitotriosidase-1 (CHIT1), chitinase-3-like protein 1 (CHI3L1), and human-specific chitinase-3-like protein 2 (CHI3L2), have emerged as markers of inflammation across the neurodegenerative spectrum, including amyotrophic lateral sclerosis (ALS).<\/jats:p>\n                  <jats:p>ALS is a fatal neuromuscular condition, and therapeutic development has been severely hindered by phenotypic heterogeneity and an incomplete understanding of aetiology. Although several overlapping disease mechanisms can contribute to neuronal death, inflammation can exacerbate pathology. Prior studies have reported that CHIT1, CHI3L1 and CHI3L2 levels are elevated in the CSF of ALS patients and associated with disease aggressiveness. Nevertheless, several open questions critical to our understanding of the role of chitinases in ALS disease burden remain: namely, (i) which cell types in the CNS are chitinase sources under physiological conditions; (ii) which of these display chitinase upregulation in ALS; and (iii) what is the diagnostic utility of the chitinases relative to established biomarkers. Here, we utilize preclinical models and post-mortem human tissue to demonstrate at both the transcriptomic and protein level that neurons are a primary source of chitinases; furthermore, neuronal chitinase expression is conserved across species. Under physiological conditions, CHI3L1 is more abundant and widely expressed across various cell types, whereas CHIT1 is predominantly expressed in neurons. Additionally, utilizing symptomatic mice from three familial ALS models, we demonstrate isoform-specific expression profiles, with astroglial and microglial upregulation of CHI3L1, and neuronal and microglial upregulation of CHIT1. Differing expression dynamics and diagnostic utility were also noted in our clinical cohort: CSF CHIT1 and CHI3L2 levels had more discriminatory power when distinguishing between ALS versus non-ALS controls, while CHI3L1 was more closely associated with inflammation and ageing across the neurodegenerative spectrum. Although the chitinases did not diagnostically outperform the neurofilament proteins, we posit that their expression profiles can inform the optimization of biomarker-guided trial design.<\/jats:p>\n                  <jats:p>Taken together, we demonstrate that chitinase upregulation in ALS is evident in various CNS cell types and that its neuronal expression may provide new insights into its role in disease activity.<\/jats:p>","DOI":"10.1093\/brain\/awag083","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T12:43:59Z","timestamp":1772109839000},"page":"3457-3474","source":"Crossref","is-referenced-by-count":1,"title":["Constitutive neuronal expression and disease-associated upregulation of chitinases in amyotrophic lateral sclerosis"],"prefix":"10.1093","volume":"149","author":[{"given":"Nayana","family":"Gaur","sequence":"first","affiliation":[{"name":"Department of Neurology , Jena University Hospital, Jena 07740 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christin","family":"Angerer","sequence":"additional","affiliation":[{"name":"Institute of Neuronal Cell Biology, School of Medicine and Health, Technical University of Munich , Munich 80802 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeynep I","family":"Gunes","sequence":"additional","affiliation":[{"name":"Institute of Clinical Neuroimmunology, Klinikum der Universit\u00e4t M\u00fcnchen, Ludwig-Maximilians University Munich , Martinsried 82152 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihai","family":"Ancau","sequence":"additional","affiliation":[{"name":"Institute of Neuronal Cell Biology, School of Medicine and Health, Technical University of Munich , Munich 80802 ,","place":["Germany"]},{"name":"Department of Neurology, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich , Munich 81675 ,","place":["Germany"]},{"name":"Munich Cluster for Systems Neurology (SyNergy) , Munich 81377 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengzhe","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Neuronal Cell Biology, School of Medicine and Health, Technical University of Munich , Munich 80802 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrick","family":"Riemenschneider","sequence":"additional","affiliation":[{"name":"Munich Cluster for Systems Neurology (SyNergy) , Munich 81377 ,","place":["Germany"]},{"name":"German Centre for Neurodegenerative Diseases (DZNE) , Munich 81377 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlene-Annett","family":"Hurler","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), LMU University Hospital, LMU Medizin, LMU Munich , Munich 81377 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Mungwa","sequence":"additional","affiliation":[{"name":"Institute of Clinical Neurobiology, University Hospital Wuerzburg , Wuerzburg 97078 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"L\u00fcningschr\u00f6r","sequence":"additional","affiliation":[{"name":"Institute of Clinical Neurobiology, University Hospital Wuerzburg , Wuerzburg 97078 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anxhela","family":"Zhiti","sequence":"additional","affiliation":[{"name":"Institute of Neuronal Cell Biology, School of Medicine and Health, Technical University of Munich , Munich 80802 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3936-6010","authenticated-orcid":false,"given":"Robert","family":"Steinbach","sequence":"additional","affiliation":[{"name":"Department of Neurology , Jena University Hospital, Jena 07740 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Briese","sequence":"additional","affiliation":[{"name":"Institute of Clinical Neurobiology, University Hospital Wuerzburg , Wuerzburg 97078 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mugdha","family":"Srivastava","sequence":"additional","affiliation":[{"name":"University of Wuerzburg Core Unit Systems Medicine, , Wuerzburg 97078 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Plaas","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine and Translational Medicine, Laboratory Animal Centre, University of Tartu , Tartu 50411 ,","place":["Estonia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7364-7791","authenticated-orcid":false,"given":"Andreas","family":"Hermann","sequence":"additional","affiliation":[{"name":"Translational Neurodegeneration Section \u2018Albrecht Kossel\u2019, Department of Neurology, University Medical Center Rostock , Rostock 18147 ,","place":["Germany"]},{"name":"German Center for Neurodegenerative Diseases (DZNE) , Greifswald 17489 and Rostock 18147 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4737-2974","authenticated-orcid":false,"given":"Michael","family":"Sendtner","sequence":"additional","affiliation":[{"name":"Institute of Clinical Neurobiology, University Hospital Wuerzburg , Wuerzburg 97078 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9634-2472","authenticated-orcid":false,"given":"Sarah","family":"J\u00e4kel","sequence":"additional","affiliation":[{"name":"Munich Cluster for Systems Neurology (SyNergy) , Munich 81377 ,","place":["Germany"]},{"name":"Institute for Stroke and Dementia Research (ISD), LMU University Hospital, LMU Medizin, LMU Munich , Munich 81377 ,","place":["Germany"]},{"name":"Klinikum Rechts der Isar, TUM School of Medicine and Health, Technical University of Munich Department of Psychiatry and Psychotherapy, , Munich 81675 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieter","family":"Edbauer","sequence":"additional","affiliation":[{"name":"Munich Cluster for Systems Neurology (SyNergy) , Munich 81377 ,","place":["Germany"]},{"name":"German Centre for Neurodegenerative Diseases (DZNE) , Munich 81377 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Herms","sequence":"additional","affiliation":[{"name":"Munich Cluster for Systems Neurology (SyNergy) , Munich 81377 ,","place":["Germany"]},{"name":"German Centre for Neurodegenerative Diseases (DZNE) , Munich 81377 ,","place":["Germany"]},{"name":"Ludwig-Maximilians-University Munich Centre for Neuropathology and Prion Research, , Munich 81377 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Liebscher","sequence":"additional","affiliation":[{"name":"Institute of Clinical Neuroimmunology, Klinikum der Universit\u00e4t M\u00fcnchen, Ludwig-Maximilians University Munich , Martinsried 82152 ,","place":["Germany"]},{"name":"Munich Cluster for Systems Neurology (SyNergy) , Munich 81377 ,","place":["Germany"]},{"name":"Biomedical Center, Ludwig-Maximilians University Munich , Martinsried 82152 ,","place":["Germany"]},{"name":"Institute of Systems Neuroscience, Medical University of Innsbruck , Innsbruck 6020 ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Grosskreutz","sequence":"additional","affiliation":[{"name":"Cluster for Precision Medicine in Inflammation, Universities of Kiel and L\u00fcbeck , Kiel 24118 ,","place":["Germany"]},{"name":"Precision Neurology of Neuromuscular and Motor Neuron Diseases, University of L\u00fcbeck , L\u00fcbeck 23538 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5422-9175","authenticated-orcid":false,"given":"Monika S","family":"Brill","sequence":"additional","affiliation":[{"name":"Institute of Neuronal Cell Biology, School of Medicine and Health, Technical University of Munich , Munich 80802 ,","place":["Germany"]},{"name":"Munich Cluster for Systems Neurology (SyNergy) , Munich 81377 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,2,28]]},"reference":[{"key":"2026100419571501200_awag083-B1","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.pathophys.2018.02.005","article-title":"Chitin, chitinases, and chitin lectins: Emerging roles in human pathophysiology","volume":"25","author":"Ziatabar","year":"2018","journal-title":"Pathophysiology"},{"key":"2026100419571501200_awag083-B2","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1186\/1471-2148-7-96","article-title":"Chitinase family GH18: Evolutionary insights from the genomic history of a diverse protein family","volume":"7","author":"Funkhouser","year":"2007","journal-title":"BMC Evol Biol"},{"key":"2026100419571501200_awag083-B3","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.jaci.2005.06.028","article-title":"Chitinases and chitinase-like proteins in T(H)2 inflammation and asthma","volume":"116","author":"Elias","year":"2005","journal-title":"J Allergy Clin Immunol"},{"key":"2026100419571501200_awag083-B4","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1177\/1352458510392619","article-title":"Chitinase effects on immune cell response in neuromyelitis optica and multiple sclerosis","volume":"17","author":"Correale","year":"2011","journal-title":"Mult Scler"},{"key":"2026100419571501200_awag083-B5","doi-asserted-by":"crossref","first-page":"33472","DOI":"10.1074\/jbc.M805574200","article-title":"Acidic mammalian chitinase is secreted via an ADAM17\/epidermal growth factor receptor-dependent pathway and stimulates chemokine production by pulmonary epithelial cells","volume":"283","author":"Hartl","year":"2008","journal-title":"J Biol Chem"},{"key":"2026100419571501200_awag083-B6","doi-asserted-by":"crossref","first-page":"e692","DOI":"10.1002\/ctm2.692","article-title":"Multi-omic landscaping of human midbrains identifies disease-relevant molecular targets and pathways in advanced-stage Parkinson\u2019s disease","volume":"12","author":"Gomes","year":"2022","journal-title":"Clin Transl Med"},{"key":"2026100419571501200_awag083-B7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/1875044301205010001","article-title":"Role of chitotriosidase (chitinase 1) under normal and disease conditions","volume":"5","author":"Kanneganti","year":"2012","journal-title":"J Epithel Biol Pharmacol"},{"key":"2026100419571501200_awag083-B8","doi-asserted-by":"crossref","first-page":"21","DOI":"10.2302\/kjm.56.21","article-title":"Role of mammalian chitinases in inflammatory conditions","volume":"56","author":"Kawada","year":"2007","journal-title":"Keio J Med"},{"key":"2026100419571501200_awag083-B9","doi-asserted-by":"crossref","first-page":"e921","DOI":"10.1212\/NXI.0000000000000921","article-title":"Chitinases and chitinase-like proteins as biomarkers in neurologic disorders","volume":"8","author":"Pinteac","year":"2021","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"2026100419571501200_awag083-B10","doi-asserted-by":"crossref","first-page":"377","DOI":"10.3389\/fneur.2020.00377","article-title":"The chitinases as biomarkers for amyotrophic lateral sclerosis: Signals from the CNS and beyond","volume":"11","author":"Gaur","year":"2020","journal-title":"Front Neurol"},{"key":"2026100419571501200_awag083-B11","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/s41582-018-0103-y","article-title":"Amyotrophic lateral sclerosis\u2014A multisystem neurodegenerative disorder","volume":"15","author":"Grossman","year":"2019","journal-title":"Nat Rev Neurol"},{"key":"2026100419571501200_awag083-B12","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1136\/jnnp-2019-322520","article-title":"Chitinases, neuroinflammation and biomarkers in ALS","volume":"91","author":"Swash","year":"2020","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"2026100419571501200_awag083-B13","doi-asserted-by":"crossref","first-page":"fcad152","DOI":"10.1093\/braincomms\/fcad152","article-title":"Spectrum and frequency of genetic variants in sporadic amyotrophic lateral sclerosis","volume":"5","author":"Ruf","year":"2023","journal-title":"Brain Commun"},{"key":"2026100419571501200_awag083-B14","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/s41576-023-00592-y","article-title":"Amyotrophic lateral sclerosis: Translating genetic discoveries into therapies","volume":"24","author":"Akcimen","year":"2023","journal-title":"Nat Rev Genet"},{"key":"2026100419571501200_awag083-B15","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1016\/S0140-6736(17)31287-4","article-title":"Amyotrophic lateral sclerosis","volume":"390","author":"van 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Neurosurg Psychiatry"},{"key":"2026100419571501200_awag083-B19","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1136\/jnnp-2019-320442","article-title":"CSF chitinase proteins in amyotrophic lateral sclerosis","volume":"90","author":"Thompson","year":"2019","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"2026100419571501200_awag083-B20","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.3390\/diagnostics11071210","article-title":"Cerebrospinal fluid chitinases as biomarkers for amyotrophic lateral sclerosis","volume":"11","author":"Costa","year":"2021","journal-title":"Diagnostics (Basel)"},{"key":"2026100419571501200_awag083-B21","first-page":"1338","article-title":"Inflammatory markers in cerebrospinal fluid: Independent prognostic biomarkers in amyotrophic lateral sclerosis?","volume":"90","author":"Gille","year":"2019","journal-title":"J Neurol Neurosurg 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