{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:53:01Z","timestamp":1790679181876,"version":"4.1.0"},"reference-count":36,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2014,2,12]],"date-time":"2014-02-12T00:00:00Z","timestamp":1392163200000},"content-version":"vor","delay-in-days":42,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Telethon Foundation","doi-asserted-by":"crossref","award":["TGT-F3"],"award-info":[{"award-number":["TGT-F3"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2014,1]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To facilitate development of novel disease\u2010modifying therapies for lysosomal storage disorder (LSDs) characterized by nervous system involvement such as metachromatic leukodystrophy (MLD), molecular markers for monitoring disease progression and therapeutic response are needed. To this end, we sought to identify blood transcripts associated with the progression of MLD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Genome\u2010wide expression analysis was performed in primary T lymphocytes of 24 patients with MLD compared to 24 age\u2010 and sex\u2010matched healthy controls. Genes associated with MLD were identified, confirmed on a quantitative polymerase chain reaction platform, and replicated in an independent patient cohort. mRNA and protein expression of the prioritized gene family of metallothioneins was evaluated in postmortem patient brains and in mouse models representing 6 other LSDs. Metallothionein expression during disease progression and in response to specific treatment was evaluated in 1 of the tested LSD mouse models. Finally, a set of in vitro studies was planned to dissect the biological functions exerted by this class of molecules.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Metallothionein genes were significantly overexpressed in T lymphocytes and brain of patients with MLD and generally marked nervous tissue damage in the LSDs here evaluated. Overexpression of metallothioneins correlated with measures of disease progression in mice and patients, whereas their levels decreased in mice upon therapeutic treatment. In vitro studies indicated that metallothionein expression is regulated in response to oxidative stress and inflammation, which are biochemical hallmarks of lysosomal storage diseases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Metallothioneins are potential markers of neurologic disease processes and treatment response in LSDs.Ann Neurol 2014;75:127\u2013137<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.24053","type":"journal-article","created":{"date-parts":[[2013,11,16]],"date-time":"2013-11-16T11:29:05Z","timestamp":1384601345000},"page":"127-137","source":"Crossref","is-referenced-by-count":20,"title":["Metallothioneins as dynamic markers for brain disease in lysosomal disorders"],"prefix":"10.1002","volume":"75","author":[{"given":"Martina","family":"Cesani","sequence":"first","affiliation":[{"name":"San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute Milan Italy"},{"name":"Neurogenomics Laboratory Harvard Medical School and Brigham &amp; Women's Hospital Cambridge MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Cavalca","sequence":"additional","affiliation":[{"name":"San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romina","family":"Macco","sequence":"additional","affiliation":[{"name":"Vita-Salute San Raffaele University Milan Italy"},{"name":"Cellular Neurophysiology Unit Division of Neuroscience, San Raffaele Scientific Institute Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Leoncini","sequence":"additional","affiliation":[{"name":"Pathology Department San Raffaele Scientific Institute Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rosa","family":"Terreni","sequence":"additional","affiliation":[{"name":"Pathology Department San Raffaele Scientific Institute Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Lorioli","sequence":"additional","affiliation":[{"name":"San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute Milan Italy"},{"name":"Vita-Salute San Raffaele University Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Furlan","sequence":"additional","affiliation":[{"name":"INSPE (Experimental Neurology Institute), Division of Neuroscience, San Raffaele Scientific Institute Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Comi","sequence":"additional","affiliation":[{"name":"Vita-Salute San Raffaele University Milan Italy"},{"name":"INSPE (Experimental Neurology Institute), Division of Neuroscience, San Raffaele Scientific Institute Milan Italy"},{"name":"Neurology Department Division of Neuroscience, San Raffaele Scientific Institute Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Doglioni","sequence":"additional","affiliation":[{"name":"Vita-Salute San Raffaele University Milan Italy"},{"name":"Pathology Department San Raffaele Scientific Institute Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Zacchetti","sequence":"additional","affiliation":[{"name":"Vita-Salute San Raffaele University Milan Italy"},{"name":"Cellular Neurophysiology Unit Division of Neuroscience, San Raffaele Scientific Institute Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Sessa","sequence":"additional","affiliation":[{"name":"San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute Milan Italy"},{"name":"Neurology Department Division of Neuroscience, San Raffaele Scientific Institute Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens R.","family":"Scherzer","sequence":"additional","affiliation":[{"name":"Neurogenomics Laboratory Harvard Medical School and Brigham &amp; 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