Fingolimod phosphate inhibits astrocyte inflammatory activity in mucolipidosis IV

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 neuropathological 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 pharmacological 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.

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

“…In non-obese diabetes EAE mice, FTY720 administration resulted in the decreased expression of reactive A1 astrocytic factors (including manganese-dependent superoxide dismutase (MnSOD), IL-6, CCL2, CXCL10, IL-1β, TNFα), and an upregulation of CXCL12 and IL-33 [65]. This effect of FTY720 on pro-inflammatory cytokines was confirmed in other rodent disease models [47,48,54,84,87,91]. Furthermore, the expression and secretion of pro-inflammatory cytokines in vitro was also reduced following treatment with FTY720 in both human and rodent primary cells from fetal and adult origin [65,73,[92][93][94] as well as in an astrocytoma cell line [95], while only one study has reported no effect of FTY720 on IL-1β and CCL2 [96].…”

Mice defective in interferon signaling help distinguish between primary and secondary pathological pathways in a mouse model of neuronal forms of Gaucher disease

“…Even though we are able to exclude a role for the IFN pathway in primary pathology, components of this pathway are nevertheless the top elevated pathway in the nGD brain and are also elevated in a number of other LSDs, including mucolipidosis type IV and Krabbe disease [32,33], along with a number of other unrelated neuroinflammatory disorders [34]. This raises the question of how this pathway is activated.…”

Early evidence of delayed oligodendrocyte maturation in the mouse model of mucolipidosis type IV

“…Based on the existing natural history data in MLIV patients and our observations in the Mcoln1 −/− mouse, MLIV can be thought of as having two distinct phases: the developmental phase, associated with early-onset delayed oligodendrocyte maturation and gliosis (Grishchuk et al, 2014;Weinstock et al, 2018), and the late degenerative phase, associated with partial loss of Purkinje cells in the MLIV mouse (Micsenyi et al, 2009) and mild cerebellar atrophy in some MLIV patients (Frei et al, 1998). Understanding the timing and mechanisms behind these distinct events is important for designing and testing therapies.…”