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Huiqing Li, Wuhong Pei, Sivia Vergarajauregui, Patricia M Zerfas, Nina Raben, Shawn M Burgess, Rosa Puertollano
Mucolipidosis type IV (MLIV) is a lysosomal storage disease characterized by neurologic and ophthalmologic abnormalities. There is currently no effective treatment. MLIV is caused by mutations in MCOLN1, a lysosomal cation channel from the transient receptor potential (TRP) family. In this study we used genome editing to knockout the two mcoln1 genes present in Dario rerio (zebrafish). Our model successfully reproduced the retinal and neuromuscular defects observed in MLIV patients, indicating that this model is suitable for studying the disease pathogenesis...
April 25, 2017: Human Molecular Genetics
Juliet R Foote, Philippe Behe, Mathew Frampton, Adam P Levine, Anthony W Segal
Neutrophils phagocytosing bacteria and fungi exhibit a burst of non-mitochondrial respiration that is required to kill and digest the engulfed microbes. This respiration is accomplished by the movement of electrons across the wall of the phagocytic vacuole by the neutrophil NADPH oxidase, NOX2. In this study, we have attempted to identify the non-proton ion channels or transporters involved in charge compensation by examining the effect of inhibitors on vacuolar pH and cross-sectional area, and on oxygen consumption...
2017: Frontiers in Pharmacology
Si Ming Man, Thirumala-Devi Kanneganti
Cysteine cathepsins are responsible for driving proteolytic degradation within the lysosome and in the extralysosomal milieu. They also have an integral role in autophagy, antigen presentation, cellular stress signaling, metabolism and lysosome-dependent cell death. Here, we discuss our findings on the role of CTSB (cathepsin B), a member of the cysteine cathepsin family, in regulating the bioavailability of lysosomes and autophagosomes and consider how this regulatory response influences host susceptibility to infectious agents...
December 2016: Autophagy
Xiaoli Zhang, Lu Yu, Haoxing Xu
Lysosomes, the cell's recycling center, undergo nutrient-sensitive adaptive changes in function and biogenesis, i.e., lysosomal adaptation. We recently discovered that lysosomes also mediate the cell's "survival" response (i.e., autophagy) to oxidative stress through the activation of TFEB (transcription factor EB), a master regulator of lysosome biogenesis and autophagy. MCOLN1/TRPML1, the principal Ca(2+) release channel on the lysosomal membrane, serves as the redox sensor in this process. Increasing reactive oxygen species (ROS) levels, either endogenously by mitochondrial damage or exogenously, directly activates MCOLN1 to induce lysosomal Ca(2+) release, triggering PPP3/calcineurin-dependent TFEB nuclear translocation to enhance autophagy...
October 2, 2016: Autophagy
Xiaoli Zhang, Xiping Cheng, Lu Yu, Junsheng Yang, Raul Calvo, Samarjit Patnaik, Xin Hu, Qiong Gao, Meimei Yang, Maria Lawas, Markus Delling, Juan Marugan, Marc Ferrer, Haoxing Xu
Cellular stresses trigger autophagy to remove damaged macromolecules and organelles. Lysosomes 'host' multiple stress-sensing mechanisms that trigger the coordinated biogenesis of autophagosomes and lysosomes. For example, transcription factor (TF)EB, which regulates autophagy and lysosome biogenesis, is activated following the inhibition of mTOR, a lysosome-localized nutrient sensor. Here we show that reactive oxygen species (ROS) activate TFEB via a lysosomal Ca(2+)-dependent mechanism independent of mTOR...
June 30, 2016: Nature Communications
Harumi Saijo, Masaharu Hayashi, Takanori Ezoe, Chihiro Ohba, Hirotomo Saitsu, Kiyoko Kurata, Naomichi Matsumoto
Mucolipidosis type IV (MLIV) is a rare neurodegenerative disorder characterized by severe psychomotor delay and visual impairment. We report the brain pathology in the first Japanese patient of MLIV with a novel homozygous missense mutation in MCOLN1. We detected the localized increase in p62-reactive astrocytes in the basal ganglia.
May 2016: Clinical Case Reports
Takashi Shiihara, Mio Watanabe, Kengo Moriyama, Yasuhiro Maruyama, Atsuo Kikuchi, Natsuko Arai-Ichinoi, Mitsugu Uematsu, Kiyoko Sameshima
BACKGROUND: Mucolipidosis IV (MLIV; OMIM #252650) is an autosomal recessive lysosomal storage disorder, frequently observed in the Ashkenazi Jewish population. MLIV typically results in intellectual disability, corneal opacities, and delayed motor milestones during infancy, with a relatively static course. To date, reports of MLIV in other ethnic groups have been sparse. PATIENT: The present study is a case report of a 9-year-old Japanese boy, diagnosed via whole-exome sequencing, with compound heterozygous mutations of MCOLN1 (OMIM(*)605248): c...
September 2016: Brain & Development
Yulia Grishchuk, Katherine G Stember, Aya Matsunaga, Ana M Olivares, Nelly M Cruz, Victoria E King, Daniel M Humphrey, Shirley L Wang, Alona Muzikansky, Rebecca A Betensky, Wallace B Thoreson, Neena Haider, Susan A Slaugenhaupt
Mucolipidosis IV is a debilitating developmental lysosomal storage disorder characterized by severe neuromotor retardation and progressive loss of vision, leading to blindness by the second decade of life. Mucolipidosis IV is caused by loss-of-function mutations in the MCOLN1 gene, which encodes the transient receptor potential channel protein mucolipin-1. Ophthalmic pathology in patients includes corneal haze and progressive retinal and optic nerve atrophy. Herein, we report ocular pathology in Mcoln1(-/-) mouse, a good phenotypic model of the disease...
January 2016: American Journal of Pathology
Natsuko Arai-Ichinoi, Mitsugu Uematsu, Ryo Sato, Tasuku Suzuki, Hiroki Kudo, Atsuo Kikuchi, Naomi Hino-Fukuyo, Mitsuyo Matsumoto, Kazuhiko Igarashi, Kazuhiro Haginoya, Shigeo Kure
T2 hyperintensity of brain white matter lesions detected by magnetic resonance imaging (MRI) are characteristic of a heterogeneous group of diseases. Persistent T2 high intensity in combination with T1 iso- or high intensity of white matter in infants indicates a lack of normal myelination, that is, hypomyelination. However, the precise diagnosis of hypomyelinating leukodystrophy based solely on MRI findings can be difficult, especially in the early stage of the disease. We studied 26 patients who were diagnosed with hypomyelinating leukodystrophy according to MRI findings and clinical features to uncover their genetic etiology through chromosomal analyses, targeted gene analyses, and an array comparative genomic hybridization (aCGH) assay...
January 2016: Human Genetics
Julie M Huynh, Hope Dang, Isabel A Munoz-Tucker, Marvin O'Ketch, Ian T Liu, Savannah Perno, Natasha Bhuyan, Allison Crain, Ivan Borbon, Hanna Fares
Mutations in MCOLN1, which encodes the cation channel protein TRPML1, result in the neurodegenerative lysosomal storage disorder Mucolipidosis type IV. Mucolipidosis type IV patients show lysosomal dysfunction in many tissues and neuronal cell death. The ortholog of TRPML1 in Caenorhabditis elegans is CUP-5; loss of CUP-5 results in lysosomal dysfunction in many tissues and death of developing intestinal cells that results in embryonic lethality. We previously showed that a null mutation in the ATP-Binding Cassette transporter MRP-4 rescues the lysosomal defect and embryonic lethality of cup-5(null) worms...
February 2016: Genetics
Yulia Grishchuk, Karina A Peña, Jessica Coblentz, Victoria E King, Daniel M Humphrey, Shirley L Wang, Kirill I Kiselyov, Susan A Slaugenhaupt
Mucolipidosis type IV (MLIV) is a lysosomal storage disease caused by mutations in the MCOLN1 gene, which encodes the lysosomal transient receptor potential ion channel mucolipin-1 (TRPML1). MLIV causes impaired motor and cognitive development, progressive loss of vision and gastric achlorhydria. How loss of TRPML1 leads to severe psychomotor retardation is currently unknown, and there is no therapy for MLIV. White matter abnormalities and a hypoplastic corpus callosum are the major hallmarks of MLIV brain pathology...
December 2015: Disease Models & Mechanisms
Math P Cuajungco, Joshua Silva, Ania Habibi, Jessica A Valadez
The discovery of the TRPML subfamily of ion channels has created an exciting niche in the fields of membrane trafficking, signal transduction, autophagy, and metal homeostasis. The TRPML protein subfamily consists of three members, TRPML1, TRPML2, and TRPML3, which are encoded by MCOLN1, MCOLN2, and MCOLN3 genes, respectively. They are non-selective cation channels with six predicted transmembrane domains and intracellular amino- and carboxyl-terminus regions. They localize to the plasma membrane, endosomes, and lysosomes of cells...
February 2016: Pflügers Archiv: European Journal of Physiology
Rob U Onyenwoke, Jonathan Z Sexton, Feng Yan, María Cristina Huertas Díaz, Lawrence J Forsberg, Michael B Major, Jay E Brenman
Autophagy is a complex pathway regulated by numerous signalling events that recycles macromolecules and may be perturbed in lysosomal storage disorders (LSDs). During autophagy, aberrant regulation of the lysosomal Ca(2+) efflux channel TRPML1 [transient receptor potential mucolipin 1 (MCOLN1)], also known as MCOLN1, is solely responsible for the human LSD mucolipidosis type IV (MLIV); however, the exact mechanisms involved in the development of the pathology of this LSD are unknown. In the present study, we provide evidence that the target of rapamycin (TOR), a nutrient-sensitive protein kinase that negatively regulates autophagy, directly targets and inactivates the TRPML1 channel and thereby functional autophagy, through phosphorylation...
September 15, 2015: Biochemical Journal
Lorraine N Clark, Robin Chan, Rong Cheng, Xinmin Liu, Naeun Park, Nancy Parmalee, Sergey Kisselev, Etty Cortes, Paola A Torres, Gregory M Pastores, Jean P Vonsattel, Roy Alcalay, Karen Marder, Lawrence L Honig, Stanley Fahn, Richard Mayeux, Michael Shelanski, Gilbert Di Paolo, Joseph H Lee
OBJECTIVE: Variants in GBA are associated with Lewy Body (LB) pathology. We investigated whether variants in other lysosomal storage disorder (LSD) genes also contribute to disease pathogenesis. METHODS: We performed a genetic analysis of four LSD genes including GBA, HEXA, SMPD1, and MCOLN1 in 231 brain autopsies. Brain autopsies included neuropathologically defined LBD without Alzheimer Disease (AD) changes (n = 59), AD without significant LB pathology (n = 71), Alzheimer disease and lewy body variant (ADLBV) (n = 68), and control brains without LB or AD neuropathology (n = 33)...
2015: PloS One
Diego L Medina, Simone Di Paola, Ivana Peluso, Andrea Armani, Diego De Stefani, Rossella Venditti, Sandro Montefusco, Anna Scotto-Rosato, Carolina Prezioso, Alison Forrester, Carmine Settembre, Wuyang Wang, Qiong Gao, Haoxing Xu, Marco Sandri, Rosario Rizzuto, Maria Antonietta De Matteis, Andrea Ballabio
The view of the lysosome as the terminal end of cellular catabolic pathways has been challenged by recent studies showing a central role of this organelle in the control of cell function. Here we show that a lysosomal Ca2+ signalling mechanism controls the activities of the phosphatase calcineurin and of its substrate ​TFEB, a master transcriptional regulator of lysosomal biogenesis and autophagy. Lysosomal Ca2+ release through ​mucolipin 1 (​MCOLN1) activates calcineurin, which binds and dephosphorylates ​TFEB, thus promoting its nuclear translocation...
March 2015: Nature Cell Biology
Xiaobing Li, Shin-Ichiroh Saitoh, Takuma Shibata, Natsuko Tanimura, Ryutaro Fukui, Kensuke Miyake
Toll-like receptor 7 (TLR7) and TLR9 sense microbial single-stranded RNA (ssRNA) and ssDNA in endolysosomes. Nucleic acid (NA)-sensing in endolysosomes is thought to be important for avoiding TLR7/9 responses to self-derived NAs. Aberrant self-derived NA transportation to endolysosomes predisposes to autoimmune diseases. To restrict NA-sensing in endolysosomes, TLR7/9 trafficking is tightly controlled by a multiple transmembrane protein Unc93B1. In contrast to TLR7/9 trafficking, little is known about a mechanism underlying NA transportation...
February 2015: International Immunology
Xiping Cheng, Xiaoli Zhang, Qiong Gao, Mohammad Ali Samie, Marlene Azar, Wai Lok Tsang, Libing Dong, Nirakar Sahoo, Xinran Li, Yue Zhuo, Abigail G Garrity, Xiang Wang, Marc Ferrer, James Dowling, Li Xu, Renzhi Han, Haoxing Xu
The integrity of the plasma membrane is maintained through an active repair process, especially in skeletal and cardiac muscle cells, in which contraction-induced mechanical damage frequently occurs in vivo. Muscular dystrophies (MDs) are a group of muscle diseases characterized by skeletal muscle wasting and weakness. An important cause of these group of diseases is defective repair of sarcolemmal injuries, which normally requires Ca(2+) sensor proteins and Ca(2+)-dependent delivery of intracellular vesicles to the sites of injury...
October 2014: Nature Medicine
Yulia Grishchuk, Sarmi Sri, Nikita Rudinskiy, Weiyuan Ma, Katherine G Stember, Matthew W Cottle, Ellen Sapp, Marian Difiglia, Alona Muzikansky, Rebecca A Betensky, Andrew M S Wong, Brian J Bacskai, Bradley T Hyman, Raymond J Kelleher, Jonathan D Cooper, Susan A Slaugenhaupt
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 [Ca(2+)]-imaging revealed no changes in resting [Ca(2+)] levels in Mcoln1(-/-) cortical neurons, implying their physiological health...
2014: Acta Neuropathologica Communications
Marisol Mirabelli-Badenier, Mariasavina Severino, Barbara Tappino, Domenico Tortora, Francesca Camia, Clelia Zanaboni, Fabia Brera, Enrico Priolo, Andrea Rossi, Roberta Biancheri, Maja Di Rocco, Mirella Filocamo
Mucolipidosis type IV (MLIV) is a very rare disorder of late endosome/lysosome transport, characterized by neurodevelopmental abnormalities and progressive visual impairment owing to corneal clouding and retinal dystrophy. Greater than 70 % of MLIV patients are of Ashkenazi Jewish ancestry. Here we report a novel MCOLN1double mutant allele [c.395_397delCTG;c.468_474dupTTGGACC] which introduces a premature stop codon [p.Ala132del; p.Asn159LeufsX27] leading to almost complete abrogation of the region coding mucolipin-1, a member of the transient receptor potential (TRP) cation channel family...
June 2015: Metabolic Brain Disease
Jaime García-Añoveros, Teerawat Wiwatpanit
The TRPML2 protein, encoded by the Mcoln2 gene, is one of the three mucolipins (TRPML1-3), a subset of the TRP superfamily of ion channels. Although there are no thorough studies on the cellular distribution of TRPML2, its mRNA appears to be largely restricted to lymphocytes and other immune cells. This contrasts with the ubiquitous expression of TRPML1 and the limited but diverse expression of TRPML3 and clearly suggests a specialized role for TRPML2 in immunity. Localization studies indicate that TRPML2 is present in lysosomes (including the specialized lysosome-related organelle that B-lymphocytes use for processing of the antigen-bound B-cell receptor), late endosomes, recycling endosomes, and, at a much lower level, the plasma membrane...
2014: Handbook of Experimental Pharmacology
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