Metallothioneins as dynamic markers for brain disease in lysosomal disorders

Martina Cesani, Eleonora Cavalca, Romina Macco, Giuseppe Leoncini, Maria Rosa Terreni, Laura Lorioli, Roberto Furlan, Giancarlo Comi, Claudio Doglioni, Daniele Zacchetti, Maria Sessa, Clemens R. Scherzer, Alessandra Biffi

Research output: Contribution to journalArticlepeer-review


Objective 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. Methods 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. Results 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. Interpretation Metallothioneins are potential markers of neurologic disease processes and treatment response in LSDs.Ann Neurol 2014;75:127-137

Original languageEnglish
Pages (from-to)127-137
Number of pages11
JournalAnnals of Neurology
Issue number1
Publication statusPublished - Jan 2014

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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