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TPP1 is well\u2010understood and, aided by animal models that accurately recapitulate the human disease, enzyme replacement therapy has been approved and other promising therapies are emerging. In contrast, there are no effective treatments for JNCL, partly because the function of the CLN3 protein remains unknown but also because animal models have attenuated disease and lack robust survival phenotypes. Mouse models for LINCL and JNCL, with mutations in <jats:italic>Tpp1<\/jats:italic> and <jats:italic>Cln3<\/jats:italic>, respectively, have been thoroughly characterized but the phenotype of a double <jats:italic>Cln3<\/jats:italic>\/<jats:italic>Tpp1<\/jats:italic> mutant remains unknown. We created this double mutant and find that its phenotype is essentially indistinguishable from the single <jats:italic>Tpp1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mutant in terms of survival and brain pathology. Analysis of brain proteomic changes in the single <jats:italic>Tpp1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> and double <jats:italic>Cln3<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>;<jats:italic>Tpp1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mutants indicates largely overlapping sets of altered proteins and reinforces earlier studies that highlight GPNMB, LYZ2, and SERPINA3 as promising biomarker candidates in LINCL while several lysosomal proteins including SMPD1 and NPC1 appear to be altered in the <jats:italic>Cln3<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> animals. An unexpected finding was that <jats:italic>Tpp1<\/jats:italic> heterozygosity significantly decreased lifespan of the <jats:italic>Cln3<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mouse. The truncated survival of this mouse model makes it potentially useful in developing therapies for JNCL using survival as an endpoint. In addition, this model may also provide insights into CLN3 protein function and its potential functional interactions with TPP1.<\/jats:p>","DOI":"10.1002\/jimd.12619","type":"journal-article","created":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T10:46:33Z","timestamp":1681987593000},"page":"720-734","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A mouse mutant deficient in both neuronal ceroid lipofuscinosis\u2010associated proteins <scp>CLN3<\/scp> and <scp>TPP1<\/scp>"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5159-9928","authenticated-orcid":false,"given":"David E.","family":"Sleat","sequence":"first","affiliation":[{"name":"Center for Advanced Biotechnology and Medicine Rutgers University  Piscataway New Jersey USA"},{"name":"Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers Biomedical Health Sciences Rutgers 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