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Heather Flanagan-Steet, Courtney Christian, Po-Nien Lu, Megan Aarnio-Peterson, Laura Sanman, Stephanie Archer-Hartmann, Parastoo Azadi, Matthew Bogyo, Richard A Steet
Cysteine cathepsins play roles during development and disease beyond their function in lysosomal protein turnover. Here, we leverage a fluorescent activity-based probe (ABP), BMV109, to track cysteine cathepsins in normal and diseased zebrafish embryos. Using this probe in a model of mucolipidosis II, we show that loss of carbohydrate-dependent lysosomal sorting alters the activity of several cathepsin proteases. The data support a pathogenic mechanism where TGF-ß signals enhance the proteolytic processing of pro-Ctsk by modulating the expression of chondroitin 4-sulfate (C4-S)...
March 13, 2018: Cell Reports
Amrita Samanta, Taylor E T Hughes, Vera Y Moiseenkova-Bell
Transient Receptor Potential (TRP) channels are evolutionarily conserved integral membrane proteins. The mammalian TRP superfamily of ion channels consists of 28 cation permeable channels that are grouped into six subfamilies based on sequence homology (Fig. 6.1). The canonical TRP (TRPC) subfamily is known for containing the founding member of mammalian TRP channels. The vanilloid TRP (TRPV) subfamily has been extensively studied due to the heat sensitivity of its founding member. The melastatin-related TRP (TRPM) subfamily includes some of the few known bi-functional ion channels, which contain functional enzymatic domains...
2018: Sub-cellular Biochemistry
Nima Kazemi, Mehrdad Asghari Estiar, Hassan Fazilaty, Ebrahim Sakhinia
Non-syndromic stuttering is a neurodevelopmental disorder characterized by disruptions in normal flow of speech in the form of repetition, prolongation and involuntary halts. Previously, mutations with more severe effects on GNPTAB and GNPTG have been reported to cause Mucolipidosisll (ML-ll) and Mucolipidosislll (ML-lll), two lysosomal storage disorders with multiple pathologies. We used homozygosity mapping and Sanger sequencing to investigate variants of the three gene in 25 Iranian families with at least two first degree related non-syndromic stutterers...
December 28, 2017: Gene
Eoin Mulroy, Andrew M Chancellor, Luciana Pelosi
PURPOSE: The mucolipidoses are rare autosomal recessive lysosomal storage disorders. Neurologic involvement in these conditions is generally thought to be limited to cognitive delay and entrapment neuropathies (primarily carpal tunnel syndrome). We sought to evaluate peripheral nerves in this condition using nerve ultrasound. METHODS: We performed peripheral nerve ultrasound in two siblings with genetically confirmed mucolipidosis type 3 (alpha/beta). RESULTS: Peripheral nerves in mucolipidosis type 3 (alpha/beta) exhibit multifocal enlargement...
February 2018: Neuroradiology
Beyhan Tüysüz, Özgür Kasapçopur, Dilek Uludağ Alkaya, Sezgin Şahin, Betül Sözeri, Gözde Yeşil
Mucolipidosis type III gamma (MLIII gamma) is a lysosomal storage disease characterized by joint stiffness, mild coarse face and corneal clouding, which becomes recognizable usually in childhood. Biallelic mutations in the GNPTG gene, which encode the γ subunit of the N-acetylglucosamine-1-phosphotransferase enzyme, are the underlying cause of MLIII gamma. The aim of this study is to evaluate the longitudinal findings and genotype of eleven patients from eight families with MLIII gamma and to establish a genotype-phenotype correlation...
February 5, 2018: Gene
Philip Schmiege, Michael Fine, Günter Blobel, Xiaochun Li
Transient receptor potential mucolipin 1 (TRPML1) is a Ca(2+)-releasing cation channel that mediates the calcium signalling and homeostasis of lysosomes. Mutations in TRPML1 lead to mucolipidosis type IV, a severe lysosomal storage disorder. Here we report two electron cryo-microscopy structures of full-length human TRPML1: a 3.72-Å apo structure at pH 7.0 in the closed state, and a 3.49-Å agonist-bound structure at pH 6.0 in an open state. Several aromatic and hydrophobic residues in pore helix 1, helices S5 and S6, and helix S6 of a neighbouring subunit, form a hydrophobic cavity to house the agonist, suggesting a distinct agonist-binding site from that found in TRPV1, a TRP channel from a different subfamily...
October 11, 2017: Nature
Qingfeng Chen, Ji She, Weizhong Zeng, Jiangtao Guo, Haoxing Xu, Xiao-Chen Bai, Youxing Jiang
Transient receptor potential mucolipin 1 (TRPML1) is a cation channel located within endosomal and lysosomal membranes. Ubiquitously expressed in mammalian cells, its loss-of-function mutations are the direct cause of type IV mucolipidosis, an autosomal recessive lysosomal storage disease. Here we present the single-particle electron cryo-microscopy structure of the mouse TRPML1 channel embedded in nanodiscs. Combined with mutagenesis analysis, the TRPML1 structure reveals that phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2) binds to the N terminus of the channel-distal from the pore-and the helix-turn-helix extension between segments S2 and S3 probably couples ligand binding to pore opening...
October 19, 2017: Nature
Marscha Hirschi, Mark A Herzik, Jinhong Wie, Yang Suo, William F Borschel, Dejian Ren, Gabriel C Lander, Seok-Yong Lee
The modulation of ion channel activity by lipids is increasingly recognized as a fundamental component of cellular signalling. The transient receptor potential mucolipin (TRPML) channel family belongs to the TRP superfamily and is composed of three members: TRPML1-TRPML3. TRPMLs are the major Ca(2+)-permeable channels on late endosomes and lysosomes (LEL). They regulate the release of Ca(2+) from organelles, which is important for various physiological processes, including organelle trafficking and fusion. Loss-of-function mutations in the MCOLN1 gene, which encodes TRPML1, cause the neurodegenerative lysosomal storage disorder mucolipidosis type IV, and a gain-of-function mutation (Ala419Pro) in TRPML3 gives rise to the varitint-waddler (Va) mouse phenotype...
October 19, 2017: Nature
Abdelali Zrhidri, Saadia Amasdl, Jaber Lyahyai, Hanane Elouardi, Bouchra Chkirate, Laure Raymond, Grégory Egéa, Mohamed Taoudi, Said El Mouatassim, Abdelaziz Sefiani
BACKGROUND: Scleroderma is a multisystem disease, characterized by fibrosis of skin and internal organs, immune dysregulation, and vasculopathy. The etiology of the disease remains unknown, but it is likely multifactorial. However, the genetic basis for this condition is defined by multiple genes that have only modest effect on disease susceptibility. METHODS: Three Moroccan siblings, born from non-consanguineous Moroccan healthy parents were referred for genetic evaluation of familial scleroderma...
September 26, 2017: Pediatric Rheumatology Online Journal
Sensen Zhang, Ningning Li, Wenwen Zeng, Ning Gao, Maojun Yang
TRPML1 channel is a non-selective group-2 transient receptor potential (TRP) channel with Ca2+ permeability. Located mainly in late endosome and lysosome of all mammalian cell types, TRPML1 is indispensable in the processes of endocytosis, membrane trafficking, and lysosome biogenesis. Mutations of TRPML1 cause a severe lysosomal storage disorder called mucolipidosis type IV (MLIV). In the present study, we determined the cryo-electron microscopy (cryo-EM) structures of Mus musculus TRPML1 (mTRPML1) in lipid nanodiscs and Amphipols...
November 2017: Protein & Cell
Nataniel Floriano Ludwig, Renata Voltolini Velho, Fernanda Sperb-Ludwig, Angelina Xavier Acosta, Erlane Marques Ribeiro, Chong A Kim, Dafne Dain Gandelman Horovitz, Raquel Boy, Maria Juliana Rodovalho-Doriqui, Charles Marques Lourenço, Emerson Santana Santos, Thomas Braulke, Sandra Pohl, Ida Vanessa D Schwartz
Mucolipidoses (ML) II and III alpha/beta are lysosomal storage diseases caused by pathogenic mutations in GNPTAB encoding the α⁄β-subunit precursor of GlcNAc-1-phosphotransferase. To determine genotype-phenotype correlation and functional analysis of mutant GlcNAc-1-phosphotransferase, 13 Brazilian patients clinically and biochemical diagnosed for MLII or III alpha/beta were studied. By sequencing of genomic GNPTAB of the MLII and MLIII alpha/beta patients we identified six novel mutations: p.D76G, p.S385L, p...
November 2017: International Journal of Biochemistry & Cell Biology
Renata Voltolini Velho, Raffaella De Pace, Sarah Klünder, Giorgia Di Lorenzo, Michaela Schweizer, Thomas Braulke, Sandra Pohl
The Golgi-resident site-1 protease (S1P) is a key regulator of cholesterol homeostasis and ER stress responses by converting latent transcription factors sterol regulatory element binding proteins (SREPBs) and activating transcription factor 6 (ATF6), as well as viral glycoproteins to their active forms. S1P is also essential for lysosome biogenesis via proteolytic activation of the hexameric GlcNAc-1-phosphotransferase complex required for modification of newly synthesized lysosomal enzymes with the lysosomal targeting signal, mannose 6-phosphate...
November 2017: Biochimica et Biophysica Acta
Simone Di Paola, Anna Scotto-Rosato, Diego Luis Medina
Efficient functioning of lysosome is necessary to ensure the correct performance of a variety of intracellular processes such as degradation of cargoes coming from the endocytic and autophagic pathways, recycling of organelles, and signaling mechanisms involved in cellular adaptation to nutrient availability. Mutations in lysosomal genes lead to more than 50 lysosomal storage disorders (LSDs). Among them, mutations in the gene encoding TRPML1 (MCOLN1) cause Mucolipidosis type IV (MLIV), a recessive LSD characterized by neurodegeneration, psychomotor retardation, ophthalmologic defects and achlorhydria...
June 24, 2017: Cell Calcium
Lauren C Boudewyn, Jakub Sikora, Ladislav Kuchar, Jana Ledvinova, Yulia Grishchuk, Shirley L Wang, Kostantin Dobrenis, Steven U Walkley
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...
September 2017: Neurobiology of Disease
Vykuntaraju K Gowda, Varun V Raghavan, Meenakshi Bhat, Asha Benakappa
No abstract text is available yet for this article.
January 2017: Journal of Pediatric Neurosciences
Sandip Patel
Lysosomes are key acidic Ca(2+) stores. The principle Ca(2+)-permeable channels of the lysosome are TRP mucolipins (TRPMLs) and NAADP-regulated two-pore channels (TPCs). Recent studies, reviewed in this collection, have linked numerous neurodegenerative diseases to both gain and loss of function of TRPMLs/TPCs, as well as to defects in acidic Ca(2+) store content. These diseases span rare lysosomal storage disorders such as Mucolipidosis Type IV and Niemann-Pick disease, type C, through to more common ones such as Alzheimer and Parkinson disease...
June 1, 2016: Messenger
Nirakar Sahoo, Mingxue Gu, Xiaoli Zhang, Neel Raval, Junsheng Yang, Michael Bekier, Raul Calvo, Samarjit Patnaik, Wuyang Wang, Greyson King, Mohammad Samie, Qiong Gao, Sasmita Sahoo, Sinju Sundaresan, Theresa M Keeley, Yanzhuang Wang, Juan Marugan, Marc Ferrer, Linda C Samuelson, Juanita L Merchant, Haoxing Xu
Gastric acid secretion by parietal cells requires trafficking and exocytosis of H/K-ATPase-rich tubulovesicles (TVs) toward apical membranes in response to histamine stimulation via cyclic AMP elevation. Here, we found that TRPML1 (ML1), a protein that is mutated in type IV mucolipidosis (ML-IV), is a tubulovesicular channel essential for TV exocytosis and acid secretion. Whereas ML-IV patients are reportedly achlorhydric, transgenic overexpression of ML1 in mouse parietal cells induced constitutive acid secretion...
May 8, 2017: Developmental Cell
Christian Grimm, Elisabeth Butz, Cheng-Chang Chen, Christian Wahl-Schott, Martin Biel
What do lysosomal storage disorders such as mucolipidosis type IV have in common with Ebola, cancer cell migration, or LDL-cholesterol trafficking? LDL-cholesterol, certain bacterial toxins and viruses, growth factors, receptors, integrins, macromolecules destined for degradation or secretion are all sorted and transported via the endolysosomal system (ES). There are several pathways known in the ES, e.g. the degradation, the recycling, or the retrograde trafficking pathway. The ES comprises early and late endosomes, lysosomes and recycling endosomes as well as autophagosomes and lysosome related organelles...
November 2017: Cell Calcium
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 Danio 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...
July 15, 2017: Human Molecular Genetics
Kirsten A Wood, Regina M Zambrano, Bradley J Cheek, Christopher Arcement, Marie Haymon, Jessica Steinkampf, Srirangan Sampath, James C Hyland, Yves Lacassie
We report on a newborn with IUGR, rhizomelic dwarfism, and suspected chondrodysplasia punctata. At birth, OI was suspected; however, a skeletal survey suggested ML II alpha/beta. Sequencing revealed compound heterozygosity for a reported pathogenic and novel but expected pathogenic GNPTAB variant. Molecular testing for autosomal recessive OI identified a SERPINF1 variant.
April 2017: Clinical Case Reports
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