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Fingolimod phosphate inhibits astrocyte inflammatory activity in mucolipidosis IV.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2018 Aug 01; Vol. 27 (15), pp. 2725-2738. - Publication Year :
- 2018
-
Abstract
- Mucolipidosis IV (MLIV) is an orphan neurodevelopmental disease that causes severe neurologic dysfunction and loss of vision. Currently there is no therapy for MLIV. It is caused by loss of function of the lysosomal channel mucolipin-1, also known as TRPML1. Knockout of the Mcoln1 gene in a mouse model mirrors clinical and neuropathologic signs in humans. Using this model, we previously observed robust activation of microglia and astrocytes in early symptomatic stages of disease. Here we investigate the consequence of mucolipin-1 loss on astrocyte inflammatory activation in vivo and in vitro and apply a pharmacologic approach to restore Mcoln1-/- astrocyte homeostasis using a clinically approved immunomodulator, fingolimod. We found that Mcoln1-/- mice over-express numerous pro-inflammatory cytokines, some of which were also over-expressed in astrocyte cultures. Changes in the cytokine profile in Mcoln1-/- astrocytes are concomitant with changes in phospho-protein signaling, including activation of PI3K/Akt and MAPK pathways. Fingolimod promotes cytokine homeostasis, down-regulates signaling within the PI3K/Akt and MAPK pathways and restores the lysosomal compartment in Mcoln1-/- astrocytes. These data suggest that fingolimod is a promising candidate for preclinical evaluation in our MLIV mouse model, which, in case of success, can be rapidly translated into clinical trial.<br /> (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Animals
Brain metabolism
Brain pathology
Cells, Cultured
Cytokines metabolism
Disease Models, Animal
Encephalitis drug therapy
Encephalitis genetics
Encephalitis metabolism
Encephalitis pathology
Female
Gene Expression Regulation
Lysosomal Membrane Proteins metabolism
Male
Mice, Knockout
Mucolipidoses drug therapy
Phosphatidylinositol 3-Kinases metabolism
Phosphoproteins metabolism
Proto-Oncogene Proteins c-akt metabolism
Transient Receptor Potential Channels genetics
Transient Receptor Potential Channels metabolism
Astrocytes drug effects
Astrocytes pathology
Brain drug effects
Fingolimod Hydrochloride pharmacology
Mucolipidoses pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 27
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 29771310
- Full Text :
- https://doi.org/10.1093/hmg/ddy182