{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:34:42Z","timestamp":1791920082177,"version":"4.3.4"},"reference-count":49,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2010,11,23]],"date-time":"2010-11-23T00:00:00Z","timestamp":1290470400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2011,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Dopaminergic neuronal death in Parkinson's disease (PD) is accompanied by oxidative stress and preceded by glutathione depletion. The development of disease\u2010modifying therapies for PD has been hindered by a paucity of animal models that mimic these features and demonstrate an age\u2010related progression. The <jats:italic>EAAC1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mouse may be useful in this regard, because <jats:italic>EAAC1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mouse neurons have impaired neuronal cysteine uptake, resulting in reduced neuronal glutathione content and chronic oxidative stress. Here we aimed to (1) characterize the age\u2010related changes in nigral dopaminergic neurons in the <jats:italic>EAAC1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mouse, and (2) use the <jats:italic>EAAC1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mouse to evaluate N\u2010acetylcysteine, a membrane\u2010permeable cysteine pro\u2010drug, as a potential disease\u2010modifying intervention for PD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Wild\u2010type mice, <jats:italic>EAAC1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice, and <jats:italic>EAAC1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice chronically treated with N\u2010acetylcysteine were evaluated at serial time points for evidence of oxidative stress, dopaminergic cell death, and motor abnormalities.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>EAAC1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice showed age\u2010dependent loss of dopaminergic neurons in the substantia nigra pars compacta, with more than 40% of these neurons lost by age 12 months. This neuronal loss was accompanied by increased nitrotyrosine formation, nitrosylated \u03b1\u2010synuclein, and microglial activation. These changes were substantially reduced in mice that received N\u2010acetylcysteine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>These findings suggest that the <jats:italic>EAAC1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mouse may be a useful model of the chronic neuronal oxidative stress that occurs in PD. The salutary effects of N\u2010acetylcysteine in this mouse model provide an impetus for clinical evaluation of glutathione repletion in PD. ANN NEUROL 2010<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.22162","type":"journal-article","created":{"date-parts":[[2010,11,23]],"date-time":"2010-11-23T19:51:18Z","timestamp":1290541878000},"page":"509-520","source":"Crossref","is-referenced-by-count":135,"title":["N\u2010acetylcysteine prevents loss of dopaminergic neurons in the <i>EAAC1<\/i><sup>\u2212\/\u2212<\/sup> mouse"],"prefix":"10.1002","volume":"69","author":[{"given":"Ari E.","family":"Berman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wai Yee","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela M.","family":"Brennan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reno C.","family":"Reyes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany 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