Mucolipin controls lysosome exocytosis in <i>Dictyostelium</i>

Lima, Wanessa Cristina; Leuba, Florence; Soldati, Thierry; Cosson, Pierre

doi:10.1242/jcs.100362

Cited by 41 publications

(52 citation statements)

References 52 publications

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“…For nuclei staining, fixed cells were incubated with DAPI for 30 min and observed with a Zeiss AxioImager Z1 photomicroscope. Internalization of fluid phase (Alexa-Fluor-647-dextran; Molecular Probes) or phagocytic particles (YG-fluorescent 1-µm latex beads; Polysciences) was performed as previously described (Lima et al, 2012) and analyzed by performing flow cytometry (FACS Calibur, Becton Dickinson). All flow cytometry data were normalized to protein content.…”

Section: Methodsmentioning

confidence: 99%

Dictyostelium EHD associates with Dynamin and participates in phagosome maturation

Gueho

Bosmani

Gopaldass

et al. 2016

Journal of Cell Science

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Proteins that contain Eps15 homology domains (EHDs) in their C-terminus are newly identified key regulators of endosomal membrane trafficking. Here, we show that D. discoideum contains a single EHD protein (referred to as EHD) that localizes to endosomal compartments and newly formed phagosomes. We provide the first evidence that EHD regulates phagosome maturation. Deletion of EHD results in defects in intraphagosomal proteolysis and acidification. These defects are linked to early delivery of lysosomal enzymes and fast retrieval of the vacuolar H + -ATPase in maturing phagosomes. We also demonstrate that EHD physically interacts with DymA. Our results indicate that EHD and DymA can associate independently with endomembranes, and yet they share identical kinetics in recruitment to phagosomes and release during phagosome maturation. Functional analysis of ehd − , dymA − and double dymA − ehd − knockout strains indicate that DymA and EHD play non-redundant and independent functions in phagosome maturation. Finally, we show that the absence of EHD leads to increased tubulation of endosomes, indicating that EHD participates in the scission of endosomal tubules, as reported for DymA.

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Section: Methodsmentioning

confidence: 99%

Dictyostelium EHD associates with Dynamin and participates in phagosome maturation

Gueho

Bosmani

Gopaldass

et al. 2016

Journal of Cell Science

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“…Previous studies by our group and others showed TRPML1 localization to late endosomes and lysosomes (LEL) [14]–[17], and its involvement in lipid trafficking [18],[19]; Ca 2+ -dependent LEL fission-fusion events [19]; reformation of lysosomes from endosome-lysosome hybrids [17],[20] and autolysosomes [21],[22]; and lysosomal exocytosis [23],[24]. However, the endogenous localization and function of TRPML1 in both neurons and glial cells in the brain have yet to be defined.…”

Section: Introductionmentioning

confidence: 99%

Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV

Grishchuk

Sri

Rudinskiy

et al. 2014

acta neuropathol commun

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Mucolipidosis IV (MLIV) is caused by mutations in the gene MCOLN1. Patients with MLIV have severe neurologic deficits and very little is known about the brain pathology in this lysosomal disease. Using an accurate mouse model of mucolipidosis IV, we observed early behavioral deficits which were accompanied by activation of microglia and astrocytes. The glial activation that persisted during the course of disease was not accompanied by neuronal loss even at the late stage. In vivo [Ca2+]-imaging revealed no changes in resting [Ca2+] levels in Mcoln1−/− cortical neurons, implying their physiological health. Despite the absence of neuron loss, we observed alterations in synaptic plasticity, as indicated by elevated paired-pulse facilitation and enhanced long-term potentiation. Myelination deficits and severely dysmorphic corpus callosum were present early and resembled white matter pathology in mucolipidosis IV patients. These results indicate the early involvement of glia, and challenge the traditional view of mucolipidosis IV as an overtly neurodegenerative condition.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0133-7) contains supplementary material, which is available to authorized users.

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“…Endosomal/lysosomal calcium egress through this TRP channel appears to have an important function in key cellular processes requiring a local, lysosomal calcium source, such as the fusion of organelles during autophagy and lysosomal exocytosis (Curcio-Morelli et al, 2010; LaPlante et al, 2006; Lima et al, 2012; Medina et al, 2015). The loss of mucolipin-1 and resulting defects in these and possibly other processes lead to a host of MLIV pathologies, including storage of cellular substrates like glycosphingolipids (GSLs) normally targeted to the lysosome for degradation, dysregulation of lysosomal pH, and the buildup of autophagosomes (Bach et al, 1975; Micsenyi et al, 2009; Venkatachalam et al, 2008; Venugopal et al, 2007; Wong et al, 2015; Ye et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, loss of mucolipin-1 secondarily leads to other abnormalities such as widespread gliosis, dysmyelination, and Purkinje cell abnormalities (Grishchuk et al, 2014; Micsenyi et al, 2009; Schiffmann et al, 2014) and death as further reported here. Numerous MLIV disease models have been generated that recapitulate cellular pathologies, including murine, Drosophila , and C. elegans models (Lima et al, 2012; Schaheen et al, 2006; Venkatachalam et al, 2008; Venugopal et al, 2007). The MLIV mouse model (Mcoln1 − / − mice) displays progressive behavioral and locomotor deficits, including hind-limb clasping, abnormal gait, and cognitive impairment (Grishchuk et al, 2014; Venugopal et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

N-butyldeoxynojirimycin delays motor deficits, cerebellar microgliosis, and Purkinje cell loss in a mouse model of mucolipidosis type IV

Boudewyn

Sikora

Kuchař

et al. 2017

Neurobiology of Disease

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Mucolipidosis type IV (MLIV) is a lysosomal storage disease exhibiting progressive intellectual disability, motor impairment, and premature death. There is currently no cure or corrective treatment. The disease results from mutations in the gene encoding mucolipin-1, a transient receptor potential channel believed to play a key role in lysosomal calcium egress. Loss of mucolipin-1 and subsequent defects lead to a host of cellular aberrations, including accumulation of glycosphingolipids (GSLs) in neurons and other cell types, microgliosis and, as reported here, cerebellar Purkinje cell loss. Several studies have demonstrated that N-butyl-deoxynojirimycin (NB-DNJ, also known as miglustat), an inhibitor of the enzyme glucosylceramide synthase (GCS), successfully delays the onset of motor deficits, improves longevity, and rescues some of the cerebellar abnormalities (e.g., Purkinje cell death) seen in another lysosomal disease known as Niemann-Pick type C (NPC). Given the similarities in pathology between MLIV and NPC, we examined whether miglustat would be efficacious in ameliorating disease progression in MLIV. Using a full mucolipin-1 knockout mouse (Mcoln1−/−), we found that early miglustat treatment delays the onset and progression of motor deficits, delays cerebellar Purkinje cell loss, and reduces cerebellar microgliosis characteristic of MLIV disease. Quantitative mass spectrometry analyses provided new data on the GSL profiles of murine MLIV brain tissue and showed that miglustat partially restored the wild type profile of white matter enriched lipids. Collectively, our findings indicate that early miglustat treatment delays the progression of clinically relevant pathology in an MLIV mouse model, and therefore supports consideration of miglustat as a therapeutic agent for MLIV disease in humans.

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Mucolipin controls lysosome exocytosis in Dictyostelium

Cited by 41 publications

References 52 publications

Dictyostelium EHD associates with Dynamin and participates in phagosome maturation

Dictyostelium EHD associates with Dynamin and participates in phagosome maturation

Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV

N-butyldeoxynojirimycin delays motor deficits, cerebellar microgliosis, and Purkinje cell loss in a mouse model of mucolipidosis type IV

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