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Background: Mucolipidosis IV (MLIV) is an autosomal recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by a loss of function of the lysosomal channel transient receptor potential mucolipin-1 and is associated with an early pro-inflammatory brain phenotype, including increased cytokine expression. The goal of the current study was to determine whether blood cytokines are linked to motor dysfunction in patients with MLIV and reflect brain inflammatory changes observed in an MLIV mouse model., Methods: To determine the relationship between blood cytokines and motor function, we collected plasma from MLIV patients and parental controls concomitantly with assessment of motor function using the Brief Assessment of Motor Function and Modified Ashworth scales. We then compared these profiles with cytokine profiles in brain and plasma samples collected from the Mcoln1 -/- mouse model of MLIV., Results: We found that MLIV patients had prominently increased cytokine levels compared to familial controls and identified profiles of cytokines correlated with motor dysfunction, including IFN-γ, IFN-α2, and IP-10. We found that IP-10 was a key differentiating factor separating MLIV cases from controls based on data from human plasma, mouse plasma, and mouse brain., Conclusions: Our data indicate that MLIV is characterized by increased blood cytokines, which are strongly related to underlying neurological and functional deficits in MLIV patients. Moreover, our data identify the interferon pro-inflammatory axis in both human and mouse signatures, suggesting that interferon signaling is an important aspect of MLIV pathology.

Mucolipidosis type IV (MLIV; OMIM 252,650) is an autosomal recessive lysosomal disorder caused by mutations in MCOLN1. MLIV causes psychomotor impairment and progressive vision loss. The major hallmarks of postnatal brain MRI are hypomyelination and thin corpus callosum. Human brain pathology data is scarce and demonstrates storage of various inclusion bodies in all neuronal cell types. The current study describes novel fetal brain MRI and neuropathology findings in a fetus with MLIV. Fetal MRI was performed at 32 and 35 weeks of gestation due to an older sibling with spastic quadriparesis, visual impairment and hypomyelination. Following abnormal fetal MRI results, the parents requested termination of pregnancy according to Israeli regulations. Fetal autopsy was performed after approval of the high committee for pregnancy termination. A genetic diagnosis of MLIV was established in the fetus and sibling. Sequential fetal brain MRI showed progressive curvilinear hypointensities on T2-weighted images in the frontal deep white matter and a thin corpus callosum. Fetal brain pathology exhibited a thin corpus callosum and hypercellular white matter composed of reactive astrocytes and microglia, multifocal white matter abnormalities with mineralized deposits, and numerous aggregates of microglia with focal intracellular iron accumulation most prominent in the frontal lobes. This is the first description in the literature of brain MRI and neuropathology in a fetus with MLIV. The findings demonstrate prenatal white matter involvement with significant activation of microglia and astrocytes and impaired iron metabolism., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mucolipidosis IV (MLIV) is an autosomal-recessive disease caused by loss-of-function mutations in the MCOLN1 gene encoding the non-selective cationic lysosomal channel transient receptor potential mucolipin-1 (TRPML1). Patients with MLIV suffer from severe motor and cognitive deficits that manifest in early infancy and progressive loss of vision leading to blindness in the second decade of life. There are no therapies available for MLIV and the unmet medical need is extremely high. Here we review the spectrum of clinical presentations and the latest research in the MLIV pre-clinical model, with the aim of highlighting the progress in understanding the pathophysiology of the disease. These highlights include elucidation of the neurodevelopmental versus neurodegenerative features over the course of disease, hypomyelination as one of the major brain pathological disease hallmarks, and dysregulation of cytokines, with emerging evidence of IFN-gamma pathway upregulation in response to TRPML1 loss and pro-inflammatory activation of astrocytes and microglia. These scientific advances in the MLIV field provide a basis for future translational research, including biomarker and therapy development, that are desperately needed for this patient population., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Mucolipidosis IV (MLIV) is an orphan disease leading to debilitating psychomotor deficits and vision loss. It is caused by loss-of-function mutations in the MCOLN1 gene that encodes the lysosomal transient receptor potential channel mucolipin1, or TRPML1. With no existing therapy, the unmet need in this disease is very high. Here, we showed that AAV-mediated CNS-targeted gene transfer of the human MCOLN1 gene rescued motor function and alleviated brain pathology in the MLIV mouse model. Using the AAV-PHP.b vector in symptomatic mice, we showed long-term reversal of declined motor function and significant delay of paralysis. Next, using self-complementary AAV9 clinical candidate vector, we showed that its intracerebroventricular administration in post-natal day 1 mice significantly improved motor function, myelination and reduced lysosomal storage load in the MLIV mouse brain. Based on our data and general advancements in the gene therapy field, we propose scAAV9-mediated CSF-targeted MCOLN1 gene transfer as a therapeutic strategy in MLIV., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Mucolipidosis type IV (MLIV), an ultra-rare neurodevelopmental and neurodegenerative disorder, is caused by mutations in the MCOLN1 gene, which encodes the late endosomal/lysosomal transient receptor potential channel TRPML1 (mucolipin 1). The precise pathophysiogical pathways that cause neurological disease in MLIV are poorly understood. Recently, the first post-mortem brain sample became available from a single MLIV patient, and in the current study we performed mass spectrometry (MS)-based proteomics on this tissue with a view to delineating pathological pathways, and to compare with previously-published data on MLIV, including studies using the Mcoln1 -/- mouse., Results: A number of pathways were altered in two brain regions from the MLIV patient, including those related to the lysosome, lipid metabolism, myelination, cellular trafficking and autophagy, mTOR and calmodulin, the complement system and interferon signaling. Of these, levels of some proteins not known previously to be associated with MLIV were altered, including APOD, PLIN4, ATG and proteins related to interferon signaling. Moreover, when proteins detected by proteomics in the human brain were compared with their orthologs detected in the Mcoln1 -/- mouse by RNAseq, the results were remarkably similar. Finally, analysis of proteins in human and mouse CSF suggest that calbindin 1 and calbindin 2 might be useful as biomarkers to help chart the course of disease development., Conclusions: Despite the sample size limitations, our findings are consistent with the relatively general changes in lysosomal function previously reported in MLIV, and shed light on new pathways of disease pathophysiology, which is required in order to understand the course of disease development and to determine the efficacy of therapies when they become available for this devastating disease.

Mucolipidosis 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., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

The transient receptor potential cation channel mucolipin 1 (TRPML1) channel is a conduit for lysosomal calcium efflux, and channel activity may be affected by lysosomal contents. The lysosomes of retinal pigmented epithelial (RPE) cells are particularly susceptible to build-up of lysosomal waste products because they must degrade the outer segments phagocytosed daily from adjacent photoreceptors; incomplete degradation leads to accumulation of lipid waste in lysosomes. This study asks whether stimulation of TRPML1 can release lysosomal calcium in RPE cells and whether such release is affected by lysosomal accumulations. The TRPML agonist ML-SA1 raised cytoplasmic calcium levels in mouse RPE cells, hesRPE cells, and ARPE-19 cells; this increase was rapid, robust, reversible, and reproducible. The increase was not altered by extracellular calcium removal or by thapsigargin but was eliminated by lysosomal rupture with glycyl-l-phenylalanine-β-naphthylamide. Treatment with desipramine to inhibit acid sphingomyelinase or YM201636 to inhibit PIKfyve also reduced the cytoplasmic calcium increase triggered by ML-SA1, whereas RPE cells from TRPML1 -/- mice showed no response to ML-SA1. Cotreatment with chloroquine and U18666A induced formation of neutral, autofluorescent lipid in RPE lysosomes and decreased lysosomal Ca 2+ release. Lysosomal Ca 2+ release was also impaired in RPE cells from the ATP-binding cassette, subfamily A, member 4 -/- mouse model of Stargardt's retinal dystrophy. Neither TRPML1 mRNA nor total lysosomal calcium levels were altered in these models, suggesting a more direct effect on the channel. In summary, stimulation of TRPML1 elevates cytoplasmic calcium levels in RPE cells, but this response is reduced by lysosomal accumulation.-Gómez, N. M., Lu, W. Lim, J. C., Kiselyov, K., Campagno, K. E., Grishchuk, Y., Slaugenhaupt, S. A., Pfeffer, B., Fliesler, S. J., Mitchell, C. H. Robust lysosomal calcium signaling through channel TRPML1 is impaired by lysosomal lipid accumulation.