Metallothioneins as dynamic markers for brain disease in lysosomal disorders

Authors

  • Martina Cesani PhD,

    1. San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy
    2. Neurogenomics Laboratory, Harvard Medical School and Brigham & Women's Hospital, Cambridge, MA, USA
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  • Eleonora Cavalca MSc,

    1. San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy
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  • Romina Macco PhD,

    1. Vita-Salute San Raffaele University, Milan, Italy
    2. Cellular Neurophysiology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
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  • Giuseppe Leoncini MD,

    1. Pathology Department, San Raffaele Scientific Institute, Milan, Italy
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  • Maria Rosa Terreni MD,

    1. Pathology Department, San Raffaele Scientific Institute, Milan, Italy
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  • Laura Lorioli MD,

    1. San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy
    2. Vita-Salute San Raffaele University, Milan, Italy
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  • Roberto Furlan MD,

    1. INSPE (Experimental Neurology Institute), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
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  • Giancarlo Comi MD,

    1. Vita-Salute San Raffaele University, Milan, Italy
    2. INSPE (Experimental Neurology Institute), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
    3. Neurology Department, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
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  • Claudio Doglioni MD,

    1. Vita-Salute San Raffaele University, Milan, Italy
    2. Pathology Department, San Raffaele Scientific Institute, Milan, Italy
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  • Daniele Zacchetti PhD,

    1. Vita-Salute San Raffaele University, Milan, Italy
    2. Cellular Neurophysiology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
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  • Maria Sessa MD,

    1. San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy
    2. Neurology Department, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
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  • Clemens R. Scherzer MD,

    1. Neurogenomics Laboratory, Harvard Medical School and Brigham & Women's Hospital, Cambridge, MA, USA
    2. Biomarkers Program, Harvard NeuroDiscovery Center, Cambridge, MA, USA
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  • Alessandra Biffi MD

    Corresponding author
    1. San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy
    • Address correspondence to Dr Biffi, San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine and Stem Cells, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. E-mail: biffi.alessandra@hsr.it, Clemens R. Scherzer, M.D.; Laboratory for Neurogenomics, Center for Neurologic Diseases, Harvard Medical School and Brigham & Women's Hospital, 65 Landsdowne Street, Suite 307A, Cambridge, MA 02139, USA; Phone: +1-617-768-8427; Fax: +1-617-768-8595; e-mail: cscherzer@rics.bwh.harvard.edu

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Abstract

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

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