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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 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.

SUBMITTER: Weinstock LD

PROVIDER: S-EPMC6915831 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Fingolimod phosphate inhibits astrocyte inflammatory activity in mucolipidosis IV.

Weinstock Laura D LD Furness Amanda M AM Herron Shawn S SS Smith Sierra S SS Sankar Sitara B SB DeRosa Samantha G SG Gao Dadi D Mepyans Molly E ME Scotto Rosato Anna A Medina Diego L DL Vardi Ayelet A Ferreira Natalia S NS Cho Soo Min SM Futerman Anthony H AH Slaugenhaupt Susan A SA Wood Levi B LB Grishchuk Yulia Y

Human molecular genetics 20180801 15

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 investi ...[more]

PMID: 29771310

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Project description:BackgroundSenescent astrocytes have been implicated in the aging brain and neurodegenerative disorders, including Parkinson's disease (PD). Astragaloside IV (AS-IV) is an antioxidant derivative from a traditional Chinese herbal medicine Astragalus membraneaceus Bunge and exerts anti-inflammatory and longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined.MethodsLong culture-induced replicative senescence model and lipopolysaccharide/1-methyl-4-phenylpyridinium (LPS/MPP+)-induced premature senescence model and a mouse model of PD were used to investigate the effect of AS-IV on astrocyte senescence in vivo and in vitro. Immunocytochemistry, qPCR, subcellular fractionation, flow cytometric analyses, and immunohistochemistry were subsequently conducted to determine the effects of AS-IV on senescence markers.ResultsWe found that AS-IV inhibited the astrocyte replicative senescence and LPS/MPP+-induced premature senescence, evidenced by decreased senescence-associated β-galactosidase activity and expression of senescence marker p16, and increased nuclear level of lamin B1, and reduced pro-inflammatory senescence-associated secretory phenotype. More importantly, we showed that AS-IV protected against the loss of dopamine neurons and behavioral deficits in the mouse model of PD, which companied by reduced accumulation of senescent astrocytes in substantia nigra compacta. Mechanistically, AS-IV promoted mitophagy, which reduced damaged mitochondria accumulation and mitochondrial reactive oxygen species generation and then contributed to the suppression of astrocyte senescence. The inhibition of autophagy abolished the suppressive effects of AS-IV on astrocyte senescence.ConclusionsOur findings reveal that AS-IV prevents dopaminergic neurodegeneration in PD via inhibition of astrocyte senescence through promoting mitophagy and suggest that AS-IV is a promising therapeutic strategy for the treatment of age-associated neurodegenerative diseases such as PD.

Project description:BACKGROUND:Lysosomal storage diseases (LSD) are a large family of inherited disorders characterized by abnormal endolysosomal accumulation of cellular material due to catabolic enzyme and transporter deficiencies. Depending on the affected metabolic pathway, LSD manifest with somatic or central nervous system (CNS) signs and symptoms. Neuroinflammation is a hallmark feature of LSD with CNS involvement such as mucolipidosis type IV, but not of others like Fabry disease. METHODS:We investigated the properties of microglia from LSD with and without major CNS involvement in 2-month-old mucolipidosis type IV (Mcoln1-/-) and Fabry disease (Glay/-) mice, respectively, by using a combination of flow cytometric, RNA sequencing, biochemical, in vitro and immunofluorescence analyses. RESULTS:We characterized microglia activation and transcriptome from mucolipidosis type IV and Fabry disease mice to determine if impaired lysosomal function is sufficient to prime these brain-resident immune cells. Consistent with the neurological pathology observed in mucolipidosis type IV, Mcoln1-/- microglia demonstrated an activation profile with a mixed neuroprotective/neurotoxic expression pattern similar to the one we previously observed in Niemann-Pick disease, type C1, another LSD with significant CNS involvement. In contrast, the Fabry disease microglia transcriptome revealed minimal alterations, consistent with the relative lack of CNS symptoms in this disease. The changes observed in Mcoln1-/- microglia showed significant overlap with alterations previously reported for other common neuroinflammatory disorders including Alzheimer's, Parkinson's, and Huntington's diseases. Indeed, our comparison of microglia transcriptomes from Alzheimer's disease, amyotrophic lateral sclerosis, Niemann-Pick disease, type C1 and mucolipidosis type IV mouse models showed an enrichment in "disease-associated microglia" pattern among these diseases. CONCLUSIONS:The similarities in microglial transcriptomes and features of neuroinflammation and microglial activation in rare monogenic disorders where the primary metabolic disturbance is known may provide novel insights into the immunopathogenesis of other more common neuroinflammatory disorders. TRIAL REGISTRATION:ClinicalTrials.gov, NCT01067742, registered on February 12, 2010.

Project description:Mucolipidosis type IV, a devastating neurological lysosomal disease linked to mutations in the transient receptor potential channel mucolipin 1, TRPML1, a calcium permeable channel in the membranes of vesicles in endolysosomal system. TRPML1 function is still being elucidated and a better understanding of the molecular pathogenesis of Mucolipidosis type IV, may facilitate development of potential treatments. We have created a model to study mucolipin function in the eukaryotic slime mould Dictyostelium discoideum by altering expression of its single mucolipin homologue, mcln. We show that in Dictyostelium mucolipin overexpression contributes significantly to global chemotactic calcium responses in vegetative and differentiated cells. Knockdown of mucolipin also enhances calcium responses in vegetative cells but does not affect responses in 6-7 h developed cells, suggesting that in developed cells mucolipin may help regulate local calcium signals rather than global calcium waves. We found that both knocking down and overexpressing mucolipin often, but not always, presented the same phenotypes. Altering mucolipin expression levels caused an accumulation or increased acidification of Lysosensor Blue stained vesicles in vegetative cells. Nutrient uptake by phagocytosis and macropinocytosis were increased but growth rates were not, suggesting defects in catabolism. Both increasing and decreasing mucolipin expression caused the formation of smaller slugs and larger numbers of fruiting bodies during multicellular development, suggesting that mucolipin is involved in initiation of aggregation centers. The fruiting bodies that formed from these smaller aggregates had proportionately larger basal discs and thickened stalks, consistent with a regulatory role for mucolipin-dependent Ca2+ signalling in the autophagic cell death pathways involved in stalk and basal disk differentiation in Dictyostelium. Thus, we have provided evidence that mucolipin contributes to chemotactic calcium signalling and that Dictyostelium is a useful model to study the molecular mechanisms involved in the cytopathogenesis of Mucolipidosis type IV.

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Fingolimod phosphate inhibits astrocyte inflammatory activity in mucolipidosis IV.

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Fingolimod phosphate inhibits astrocyte inflammatory activity in mucolipidosis IV.

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