Metallothioneins as dynamic markers for brain disease in lysosomal disorders
Article first published online: 12 FEB 2014
© 2014 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association
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Annals of Neurology
Volume 75, Issue 1, pages 127–137, January 2014
How to Cite
Cesani, M., Cavalca, E., Macco, R., Leoncini, G., Terreni, M. R., Lorioli, L., Furlan, R., Comi, G., Doglioni, C., Zacchetti, D., Sessa, M., Scherzer, C. R. and Biffi, A. (2014), Metallothioneins as dynamic markers for brain disease in lysosomal disorders. Ann Neurol., 75: 127–137. doi: 10.1002/ana.24053
- Issue published online: 12 FEB 2014
- Article first published online: 12 FEB 2014
- Accepted manuscript online: 16 NOV 2013 06:12AM EST
- Manuscript Accepted: 30 OCT 2013
- Manuscript Revised: 17 OCT 2013
- Manuscript Received: 12 NOV 2012
- Italian Telethon Foundation (TGT-F3; A.B.)
- Italian Ministry of Health (Progetto Giovani Ricercatori, A.B.)
- NIH. Grant Number: R01NS064155, R21NS060227, P01NS058793
- US Department of Defense. Grant Number: W81XWH-13-1-0115
To facilitate development of novel disease-modifying 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.
Genome-wide expression analysis was performed in primary T lymphocytes of 24 patients with MLD compared to 24 age- and sex-matched 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.
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.
Metallothioneins are potential markers of neurologic disease processes and treatment response in LSDs.Ann Neurol 2014;75:127–137