{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T22:26:54Z","timestamp":1759616814071},"reference-count":52,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2015,11,6]],"date-time":"2015-11-06T00:00:00Z","timestamp":1446768000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Oxidative stress in the brain is highly prevalent in many neurodegenerative disorders including lysosomal storage disorders, in which neurodegeneration is a devastating manifestation. Despite intense studies, a precise mechanism linking oxidative stress to neuropathology in specific neurodegenerative diseases remains largely unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative lysosomal storage disease caused by mutations in the ceroid lipofuscinosis neuronal\u20101 (<jats:italic><jats:styled-content style=\"fixed-case\">CLN<\/jats:styled-content>1<\/jats:italic>) gene encoding palmitoyl\u2010protein thioesterase\u20101. Previously, we reported that in the brain of <jats:italic>Cln1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice, which mimic <jats:styled-content style=\"fixed-case\">INCL<\/jats:styled-content>, and in postmortem brain tissues from <jats:styled-content style=\"fixed-case\">INCL<\/jats:styled-content> patients, increased oxidative stress is readily detectable. We used molecular, biochemical, immunohistological, and electrophysiological analyses of brain tissues of <jats:italic>Cln1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice to study the role(s) of oxidative stress in mediating neuropathology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our results show that in <jats:italic>Cln1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice oxidative stress in the brain via upregulation of the transcription factor, <jats:styled-content style=\"fixed-case\">CCAAT<\/jats:styled-content>\/enhancer\u2010binding protein\u2010<jats:italic>\u03b4<\/jats:italic>, stimulated expression of serpina1, which is an inhibitor of a serine protease, neurotrypsin. Moreover, in the <jats:italic>Cln1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice, suppression of neurotrypsin activity by serpina1 inhibited the cleavage of agrin (a large proteoglycan), which substantially reduced the production of agrin\u201022, essential for synaptic homeostasis. Direct whole\u2010cell recordings at the nerve terminals of <jats:italic>Cln1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice showed inhibition of Ca<jats:sup>2+<\/jats:sup> currents attesting to synaptic dysfunction. Treatment of these mice with a thioesterase\u2010mimetic small molecule, <jats:italic>N<\/jats:italic>\u2010tert (Butyl) hydroxylamine (NtBu<jats:styled-content style=\"fixed-case\">HA<\/jats:styled-content>), increased agrin\u201022 levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our findings provide insight into a novel pathway linking oxidative stress with synaptic pathology in <jats:italic>Cln1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice and suggest that NtBu<jats:styled-content style=\"fixed-case\">HA<\/jats:styled-content>, which increased agrin\u201022 levels, may ameliorate synaptic dysfunction in this devastating neurodegenerative disease.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.261","type":"journal-article","created":{"date-parts":[[2015,11,7]],"date-time":"2015-11-07T22:05:33Z","timestamp":1446933933000},"page":"1085-1104","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Suppression of agrin\u201022 production and synaptic dysfunction in <i>Cln1<\/i><sup><i>\u2212\/\u2212<\/i><\/sup> mice"],"prefix":"10.1002","volume":"2","author":[{"given":"Shiyong","family":"Peng","sequence":"first","affiliation":[{"name":"Section on Developmental Genetics Program on Developmental Endocrinology and Genetics Eunice Kennedy\u2010Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892\u20101830"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhua","family":"Xu","sequence":"additional","affiliation":[{"name":"Synaptic Transmission Section (HNQ23\u2010R) National Institute of Neurological Disorders and Stroke NIH Bethesda Maryland 20892"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth A.","family":"Pelkey","sequence":"additional","affiliation":[{"name":"The Program in Developmental Neuroscience Eunice Kennedy\u2010Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892\u20103715"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Goutam","family":"Chandra","sequence":"additional","affiliation":[{"name":"Section on Developmental Genetics Program on Developmental Endocrinology and Genetics Eunice Kennedy\u2010Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892\u20101830"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhongjian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Section on Developmental Genetics Program on Developmental Endocrinology and Genetics Eunice Kennedy\u2010Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892\u20101830"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria B.","family":"Bagh","sequence":"additional","affiliation":[{"name":"Section on Developmental Genetics Program on Developmental Endocrinology and Genetics Eunice Kennedy\u2010Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892\u20101830"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoqing","family":"Yuan","sequence":"additional","affiliation":[{"name":"The Program in Developmental Neuroscience Eunice Kennedy\u2010Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892\u20103715"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling\u2010Gang","family":"Wu","sequence":"additional","affiliation":[{"name":"Synaptic Transmission Section (HNQ23\u2010R) National Institute of Neurological Disorders and Stroke NIH Bethesda Maryland 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