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Metallothioneins are neuroprotective agents in lysosomal storage disorders
Author(s) -
Cavalca Eleonora,
Cesani Martina,
Gifford Jennifer C.,
Sena-Esteves Miguel,
Terreni Maria Rosa,
Leoncini Giuseppe,
Peviani Marco,
Biffi Alessandra
Publication year - 2018
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25161
Subject(s) - neuroprotection , microglia , lysosomal storage disease , phenotype , transgene , genetically modified mouse , genetic enhancement , neurodegeneration , central nervous system , biology , disease , oxidative stress , neuronal ceroid lipofuscinosis , pharmacology , neuroscience , immunology , medicine , gene , pathology , inflammation , endocrinology , genetics
Objective Lysosomal storage disorders (LSDs) are a broad class of inherited metabolic diseases caused by the defective activity of lysosomal enzymes. Central nervous system (CNS) manifestations are present in roughly 50% of LSD patients and represent an unmet medical need for them. We explored the therapeutic potential of metallothioneins (MTs), a newly identified family of proteins with reported neuroprotective roles, in the murine models of two LSDs with CNS involvement. Methods MT‐1 overexpressing transgenic mice (MTtg) were crossed with the murine models of Batten and Krabbe diseases. Changes in the survival and manifestations of the disease in the MTtg setting were assessed. In addition, we analyzed the therapeutic effects of MT‐1 CNS gene delivery in one of these LSD models. Results Constitutive expression of MT‐1 exerted favorable phenotypic effects in both LSD models. MT‐LSD mice showed a 5% to 10% increase in survival and slower disease progression as compared to not‐transgenic LSD mice. Rescue of Purkinje cells from degeneration and apoptosis was also observed in the MT‐LSD models. This phenotypic amelioration was accompanied by a modulation of the disease‐associated activated inflammatory microglia phenotype, and by a reduction of oxidative stress. Importantly, for the clinical translation of our findings, the very same effects were obtained when MTs were delivered to brains by systemic AAV gene transfer. Interpretation MTs can be considered novel therapeutic agents (and targets) in LSDs and potentiate the effects of approaches aiming at correction of the disease‐causing enzyme deficiency in the CNS. Ann Neurol 2018;83:418–432 Ann Neurol 2018;83:418–432