Molecular elucidation of brain lipofuscin in aging and Neuronal Ceroid Lipofuscinosis

Molecular elucidation of brain lipofuscin in aging and Neuronal Ceroid Lipofuscinosis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Molecular elucidation of brain lipofuscin in aging and Neuronal Ceroid Lipofuscinosis Sofia Massaro Tieze, Alexander Esqueda, Rachel McAllister, Matija Lagator, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6010379/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Lipofuscin is an autofluorescent material that accrues in brain tissues with age and in Neuronal Ceroid Lipofuscinosis (NCL), a neurodegenerative disease with pediatric onset. The distribution, composition, and organellar origin of lipofuscin have remained unclear despite its widespread presence in aged tissues and involvement in neurodegeneration. Here, we elucidate lipofuscin composition and report the spatiotemporal dynamics of lipofuscin accumulation in aging and NCL on a neuroanatomical atlas. Multimodal mass spectrometry, ultrastructural analyses, and assays of metabolic flux identify a primary role of the lysosomal-mitochondrial axis in lipofuscin formation. Dissection of implicated molecular pathways reveals protein S-acylation and lipid homeostasis as central processes involved in aging and NCL. Biological sciences/Neuroscience/Molecular neuroscience Biological sciences/Neuroscience/Neural ageing Biological sciences/Neuroscience/Diseases of the nervous system/Neurodegeneration Health sciences/Biomarkers/Predictive markers Biological sciences/Chemical biology/Post-translational modifications Full Text Additional Declarations There is NO Competing Interest. Supplementary Files DataS3.pdf Data S3 DataS2.pdf Data S2 DataS1.pdf Data S1 DocumentS1Tiezeetal.SupplementalFigures.pdf Document S1_Supplemental Figures Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6010379","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":430556767,"identity":"5bcfbf87-b821-4b1e-86a1-040945cc93af","order_by":0,"name":"Sofia Massaro Tieze","email":"","orcid":"","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"Sofia","middleName":"Massaro","lastName":"Tieze","suffix":""},{"id":430556768,"identity":"926e3331-fa84-4566-aa69-ae5be2822b5b","order_by":1,"name":"Alexander Esqueda","email":"","orcid":"","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Esqueda","suffix":""},{"id":430556769,"identity":"696bf30c-b201-4db4-9fff-b97f4f1617f6","order_by":2,"name":"Rachel McAllister","email":"","orcid":"","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"Rachel","middleName":"","lastName":"McAllister","suffix":""},{"id":430556770,"identity":"2fe74490-00a1-4393-9e84-3b0ebce245f0","order_by":3,"name":"Matija Lagator","email":"","orcid":"https://orcid.org/0000-0001-8301-8908","institution":"University of Manchester","correspondingAuthor":false,"prefix":"","firstName":"Matija","middleName":"","lastName":"Lagator","suffix":""},{"id":430556771,"identity":"0733f322-c2da-470d-8b2f-a88357e362b2","order_by":4,"name":"Betül Yücel","email":"","orcid":"","institution":"Yale University","correspondingAuthor":false,"prefix":"","firstName":"Betül","middleName":"","lastName":"Yücel","suffix":""},{"id":430556772,"identity":"291213ca-dc70-4d6b-b506-71940ab98086","order_by":5,"name":"Eric Sun","email":"","orcid":"","institution":"Yale College","correspondingAuthor":false,"prefix":"","firstName":"Eric","middleName":"","lastName":"Sun","suffix":""},{"id":430556773,"identity":"5f9daea6-1f18-42c6-9e8f-c423633e83c2","order_by":6,"name":"TuKiet T. 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