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

2020 ◽  
Vol 13 (7) ◽  
pp. dmm044230 ◽  
Author(s):  
Molly Mepyans ◽  
Livia Andrzejczuk ◽  
Jahree Sosa ◽  
Sierra Smith ◽  
Shawn Herron ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transient Receptor Potential ◽  
Vision Loss ◽  
Cerebellar Atrophy ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Lysosomal Disease ◽  
Mucolipidosis Type Iv ◽  
Type Iv ◽  
Mucolipidosis Type

ABSTRACTMucolipidosis type IV (MLIV) is a lysosomal disease caused by mutations in the MCOLN1 gene that encodes the endolysosomal transient receptor potential channel mucolipin-1, or TRPML1. MLIV results in developmental delay, motor and cognitive impairments, and vision loss. Brain abnormalities include thinning and malformation of the corpus callosum, white-matter abnormalities, accumulation of undegraded intracellular ‘storage’ material and cerebellar atrophy in older patients. Identification of the early events in the MLIV course is key to understanding the disease and deploying therapies. The Mcoln1−/− mouse model reproduces all major aspects of the human disease. We have previously reported hypomyelination in the MLIV mouse brain. Here, we investigated the onset of hypomyelination and compared oligodendrocyte maturation between the cortex/forebrain and cerebellum. We found significant delays in expression of mature oligodendrocyte markers Mag, Mbp and Mobp in the Mcoln1−/− cortex, manifesting as early as 10 days after birth and persisting later in life. Such delays were less pronounced in the cerebellum. Despite our previous finding of diminished accumulation of the ferritin-bound iron in the Mcoln1−/− brain, we report no significant changes in expression of the cytosolic iron reporters, suggesting that iron-handling deficits in MLIV occur in the lysosomes and do not involve broad iron deficiency. These data demonstrate very early deficits of oligodendrocyte maturation and critical regional differences in myelination between the forebrain and cerebellum in the mouse model of MLIV. Furthermore, they establish quantitative readouts of the MLIV impact on early brain development, useful to gauge efficacy in pre-clinical trials.

Mucolipidosis type IV and the mucolipins

2010 ◽  
Vol 38 (6) ◽  
pp. 1432-1435 ◽  
Author(s):  
Gideon Bach ◽  
David A. Zeevi ◽  
Ayala Frumkin ◽  
Aviram Kogot-Levin
Keyword(s):  
Cellular Localization ◽  
Transient Receptor Potential ◽  
Physiological Role ◽  
Receptor Potential ◽  
Lysosomal Storage ◽  
Additional Function ◽  
Mucolipidosis Type Iv ◽  
Type Iv ◽  
Early Endosomes ◽  
Mucolipidosis Type

MLIV (mucolipidosis type IV) is a neurodegenerative lysosomal storage disorder caused by mutations in MCOLN1, a gene that encodes TRPML1 (mucolipin-1), a member of the TRPML (transient receptor potential mucolipin) cation channels. Two additional homologues are TRPML2 and TRPML3 comprising the TRPML subgroup in the TRP superfamily. The three proteins play apparently key roles along the endocytosis process, and thus their cellular localization varies among the different group members. Thus TRPML1 is localized exclusively to late endosomes and lysosomes, TRPML2 is primarily located in the recycling clathrin-independent GPI (glycosylphosphatidylinositol)-anchored proteins and early endosomes, and TRPML3 is primarily located in early endosomes. Apparently, all three proteins' main physiological function underlies Ca2+ channelling, regulating the endocytosis process. Recent findings also indicate that the three TRPML proteins form heteromeric complexes at least in some of their cellular content. The physiological role of these complexes in lysosomal function remains to be elucidated, as well as their effect on the pathophysiology of MLIV. Another open question is whether any one of the TRPMLs bears additional function in channel activity

scholarly journals Neuropathology of the Mcoln1−/− Knockout Mouse Model of Mucolipidosis Type IV

2009 ◽  
Vol 68 (2) ◽  
pp. 125-135 ◽  
Author(s):  
Matthew C. Micsenyi ◽  
Kostantin Dobrenis ◽  
Gloria Stephney ◽  
James Pickel ◽  
Marie T. Vanier ◽  
...  
Keyword(s):  
Mouse Model ◽  
Knockout Mouse ◽  
Knockout Mouse Model ◽  
Mucolipidosis Type Iv ◽  
Type Iv ◽  
Mucolipidosis Type

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

2017 ◽  
Vol 105 ◽  
pp. 257-270 ◽  
Author(s):  
Lauren C. Boudewyn ◽  
Jakub Sikora ◽  
Ladislav Kuchar ◽  
Jana Ledvinova ◽  
Yulia Grishchuk ◽  
...  
Keyword(s):  
Mouse Model ◽  
Purkinje Cell ◽  
Cell Loss ◽  
Motor Deficits ◽  
Mucolipidosis Type Iv ◽  
Type Iv ◽  
Purkinje Cell Loss ◽  
Mucolipidosis Type

scholarly journals Membrane traffic and turnover in TRP-ML1–deficient cells: a revised model for mucolipidosis type IV pathogenesis

2008 ◽  
Vol 205 (6) ◽  
pp. 1477-1490 ◽  
Author(s):  
Mark T. Miedel ◽  
Youssef Rbaibi ◽  
Christopher J. Guerriero ◽  
Grace Colletti ◽  
Kelly M. Weixel ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Degradation Kinetics ◽  
Density Lipoprotein ◽  
Membrane Traffic ◽  
Cumulative Effect ◽  
Lysosomal Storage ◽  
Mucolipidosis Type Iv ◽  
Type Iv ◽  
Kinetics Of ◽  
Mucolipidosis Type

The lysosomal storage disorder mucolipidosis type IV (MLIV) is caused by mutations in the transient receptor potential–mucolipin-1 (TRP-ML1) ion channel. The “biogenesis” model for MLIV pathogenesis suggests that TRP-ML1 modulates postendocytic delivery to lysosomes by regulating interactions between late endosomes and lysosomes. This model is based on observed lipid trafficking delays in MLIV patient fibroblasts. Because membrane traffic aberrations may be secondary to lipid buildup in chronically TRP-ML1–deficient cells, we depleted TRP-ML1 in HeLa cells using small interfering RNA and examined the effects on cell morphology and postendocytic traffic. TRP-ML1 knockdown induced gradual accumulation of membranous inclusions and, thus, represents a good model in which to examine the direct effects of acute TRP-ML1 deficiency on membrane traffic. Ratiometric imaging revealed decreased lysosomal pH in TRP-ML1–deficient cells, suggesting a disruption in lysosomal function. Nevertheless, we found no effect of TRP-ML1 knockdown on the kinetics of protein or lipid delivery to lysosomes. In contrast, by comparing degradation kinetics of low density lipoprotein constituents, we confirmed a selective defect in cholesterol but not apolipoprotein B hydrolysis in MLIV fibroblasts. We hypothesize that the effects of TRP-ML1 loss on hydrolytic activity have a cumulative effect on lysosome function, resulting in a lag between TRP-ML1 loss and full manifestation of MLIV.

scholarly journals Multi-Species Phenotypic Screening across Disease Models of Mucolipidosis Type IV

2021 ◽  
Author(s):  
Andrea Hadjikyriacou ◽  
Sangeetha Iyer ◽  
Joshua D. Mast ◽  
Nina DiPrimio ◽  
John Concannon ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Transient Receptor Potential ◽  
Model Organisms ◽  
Disease Models ◽  
Cyclin Dependent Kinase ◽  
Chemical Probes ◽  
Mucolipidosis Type Iv ◽  
Type Iv ◽  
Invertebrate Model ◽  
Mucolipidosis Type

AbstractInvertebrate model organisms (the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster) are valuable tools to bridge the gap between traditional in vitro discovery and preclinical animal models. Invertebrate model organisms are poised to serve as better disease models than 2D cellular monocultures for drug discovery, as well as easier and more cost-effective to scale up than 3D organoids/assembloids or co-cultures. A strength of model organisms is the opportunity to probe conserved biology such as lysosomal function and autophagy in a physiological setting. However, invertebrate models are not without pharmacokinetic and pharmacodynamic challenges, such as poor tissue penetration and confidence in a compound’s mechanism of action. To confront those challenges, we took advantage of the Novartis mechanism-of-action box (MoA Box), a compound library of well-annotated and drug-like chemical probes. Curious as to how the MoA Box, comprised of chemical probes optimized for mammalian targets, would fare in an invertebrate setting we screened the MoA Box across three different models of the lysosomal storage disease mucolipidosis Type IV (MLIV). MLIV is caused by mutations in the lysosomal transient receptor potential ion channel mucolipin-1 (TRPML1) resulting in hyper-acidic lysosomes and dysregulated autophagy. The overlap of screening hits from worm, fly, and patient fibroblast screens identified cyclin-dependent kinase (CDK) inhibition as an evolutionarily conserved disease modifier and potential drug repurposing strategy.Summary statementA trio of phenotypic screens across Drosophila, C. elegans, and H. sapiens models of mucolipidosis IV was performed and identified overlapping hits including cyclin-dependent kinase inhibitors.

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