Metallothioneins as dynamic markers for brain disease in lysosomal disorders.
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.


CONCLUSIONS
Metallothioneins are potential markers of neurologic disease processes and treatment response in LSDs.
San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy; Neurogenomics Laboratory, Harvard Medical School and Brigham & Women's Hospital, Cambridge, MA, USA.
Martina
M
Cesani
Eleonora
E
Cavalca
Romina
R
Macco
Giuseppe
G
Leoncini
Maria Rosa
MR
Terreni
Laura
L
Lorioli
Roberto
R
Furlan
Giancarlo
G
Comi
Claudio
C
Doglioni
Daniele
D
Zacchetti
Maria
M
Sessa
Clemens R
CR
Scherzer
Alessandra
A
Biffi
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D018920:Coculture Techniques; D004195:Disease Models, Animal; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D007966:Leukodystrophy, Metachromatic / Q000175:diagnosis / Q000378:metabolism*; D016464:Lysosomal Storage Diseases / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D008668:Metallothionein / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D056004:Molecular Dynamics Simulation; D061251:Primary Cell Culture
D015415:Biomarkers; D008668:Metallothionein