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1.
Sci Rep ; 7(1): 11260, 2017 09 12.
Article in English | MEDLINE | ID: mdl-28900161

ABSTRACT

Coenzyme A is an essential metabolite known for its central role in over one hundred cellular metabolic reactions. In cells, Coenzyme A is synthesized de novo in five enzymatic steps with vitamin B5 as the starting metabolite, phosphorylated by pantothenate kinase. Mutations in the pantothenate kinase 2 gene cause a severe form of neurodegeneration for which no treatment is available. One therapeutic strategy is to generate Coenzyme A precursors downstream of the defective step in the pathway. Here we describe the synthesis, characteristics and in vivo rescue potential of the acetyl-Coenzyme A precursor S-acetyl-4'-phosphopantetheine as a possible treatment for neurodegeneration associated with pantothenate kinase deficiency.


Subject(s)
Heredodegenerative Disorders, Nervous System/drug therapy , Pantetheine/analogs & derivatives , Phosphotransferases (Alcohol Group Acceptor)/deficiency , Serum/chemistry , Animals , Cell Line , Disease Models, Animal , Drosophila , Humans , Mice , Pantetheine/administration & dosage , Pantetheine/chemical synthesis , Pantetheine/isolation & purification , Pantetheine/pharmacokinetics , Treatment Outcome
2.
Nat Chem Biol ; 11(10): 784-92, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26322826

ABSTRACT

The metabolic cofactor coenzyme A (CoA) gained renewed attention because of its roles in neurodegeneration, protein acetylation, autophagy and signal transduction. The long-standing dogma is that eukaryotic cells obtain CoA exclusively via the uptake of extracellular precursors, especially vitamin B5, which is intracellularly converted through five conserved enzymatic reactions into CoA. This study demonstrates an alternative mechanism that allows cells and organisms to adjust intracellular CoA levels by using exogenous CoA. Here CoA was hydrolyzed extracellularly by ectonucleotide pyrophosphatases to 4'-phosphopantetheine, a biologically stable molecule able to translocate through membranes via passive diffusion. Inside the cell, 4'-phosphopantetheine was enzymatically converted back to CoA by the bifunctional enzyme CoA synthase. Phenotypes induced by intracellular CoA deprivation were reversed when exogenous CoA was provided. Our findings answer long-standing questions in fundamental cell biology and have major implications for the understanding of CoA-related diseases and therapies.


Subject(s)
Caenorhabditis elegans/metabolism , Coenzyme A/biosynthesis , Drosophila/metabolism , Pantetheine/analogs & derivatives , Animals , Caenorhabditis elegans/growth & development , Cell Line , Coenzyme A/blood , Coenzyme A/pharmacology , Coenzyme A Ligases/metabolism , Drosophila/cytology , Drosophila/growth & development , Female , HEK293 Cells , Humans , Longevity/physiology , Male , Mice, Inbred C57BL , Pantetheine/blood , Pantetheine/metabolism , Pantetheine/pharmacology , Phosphotransferases (Alcohol Group Acceptor)/genetics , Phosphotransferases (Alcohol Group Acceptor)/metabolism
3.
J Cell Biol ; 208(3): 313-29, 2015 Feb 02.
Article in English | MEDLINE | ID: mdl-25646087

ABSTRACT

Fast neural conduction requires accumulation of Na(+) channels at nodes of Ranvier. Dedicated adhesion molecules on myelinating cells and axons govern node organization. Among those, specific laminins and dystroglycan complexes contribute to Na(+) channel clustering at peripheral nodes by unknown mechanisms. We show that in addition to facing the basal lamina, dystroglycan is found near the nodal matrix around axons, binds matrix components, and participates in initial events of nodogenesis. We identify the dystroglycan-ligand perlecan as a novel nodal component and show that dystroglycan is required for the selective accumulation of perlecan at nodes. Perlecan binds the clustering molecule gliomedin and enhances clustering of node of Ranvier components. These data show that proteoglycans have specific roles in peripheral nodes and indicate that peripheral and central axons use similar strategies but different molecules to form nodes of Ranvier. Further, our data indicate that dystroglycan binds free matrix that is not organized in a basal lamina.


Subject(s)
Cell Adhesion Molecules, Neuronal/metabolism , Heparan Sulfate Proteoglycans/metabolism , Ranvier's Nodes/metabolism , Animals , Cells, Cultured , Coculture Techniques , Dystroglycans/metabolism , Extracellular Matrix/metabolism , Humans , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Transgenic , Microvilli/metabolism , Protein Binding , Protein Transport , Proteolysis , Sodium Channels/metabolism
4.
J Inherit Metab Dis ; 38(1): 123-36, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25300979

ABSTRACT

Neurodegeneration with brain iron accumulation (NBIA) is a group of devastating and life threatening rare diseases. Adult and early-onset NBIA syndromes are inherited as X-chromosomal, autosomal dominant or recessive traits and several genes have been identified as responsible for these disorders. Among the identified disease genes, only two code for proteins directly involved in iron metabolism while the remaining NBIA genes encode proteins with a wide variety of functions ranging from fatty acid metabolism and autophagy to still unknown activities. It is becoming increasingly evident that many neurodegenerative diseases are associated with metabolic dysfunction that often involves altered lipid metabolism. This is not surprising since neurons have a peculiar and heterogeneous lipid composition critical for the development and correct functioning of the nervous system. This review will focus on specific NBIA forms, namely PKAN, CoPAN, PLAN, FAHN and MPAN, which display an interesting link between neurodegeneration and alteration of phospholipids and sphingolipids metabolism, mitochondrial morphology and membrane remodelling.


Subject(s)
Brain/metabolism , Iron Metabolism Disorders/metabolism , Iron/chemistry , Lipid Metabolism , Neuroaxonal Dystrophies/metabolism , Neurodegenerative Diseases/metabolism , Animals , Fatty Acids/metabolism , Humans , Iron Metabolism Disorders/genetics , Mitochondria/metabolism , Mixed Function Oxygenases/metabolism , Neuroaxonal Dystrophies/genetics , Neurodegenerative Diseases/genetics , Pantothenate Kinase-Associated Neurodegeneration/genetics , Pantothenate Kinase-Associated Neurodegeneration/metabolism , Phospholipids/metabolism , Sphingolipids/metabolism , Syndrome
5.
Acta Neuropathol ; 129(1): 97-113, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25421425

ABSTRACT

Macrophages contribute to peripheral nerve regeneration and produce collagen VI, an extracellular matrix protein involved in nerve function. Here, we show that collagen VI is critical for macrophage migration and polarization during peripheral nerve regeneration. Nerve injury induces a robust upregulation of collagen VI, whereas lack of collagen VI in Col6a1(-/-) mice delays peripheral nerve regeneration. In vitro studies demonstrated that collagen VI promotes macrophage migration and polarization via AKT and PKA pathways. Col6a1(-/-) macrophages exhibit impaired migration abilities and reduced antiinflammatory (M2) phenotype polarization, but are prone to skewing toward the proinflammatory (M1) phenotype. In vivo, macrophage recruitment and M2 polarization are impaired in Col6a1(-/-) mice after nerve injury. The delayed nerve regeneration of Col6a1(-/-) mice is induced by macrophage deficits and rejuvenated by transplantation of wild-type bone marrow cells. These results identify collagen VI as a novel regulator for peripheral nerve regeneration by modulating macrophage function.


Subject(s)
Collagen Type VI/metabolism , Macrophages/physiology , Nerve Regeneration/physiology , Sciatic Nerve/physiology , Animals , Blotting, Western , Bone Marrow Transplantation , Cell Line , Cell Movement/physiology , Collagen Type VI/genetics , Disease Models, Animal , Immunohistochemistry , Mice , Mice, Inbred C57BL , Mice, Knockout , Sciatic Nerve/injuries
6.
J Neurosci ; 31(34): 12208-17, 2011 Aug 24.
Article in English | MEDLINE | ID: mdl-21865464

ABSTRACT

Myelinating glial cells exhibit a spectacular cytoarchitecture, because they polarize on multiple axes and domains. How this occurs is essentially unknown. The dystroglycan-dystrophin complex is required for the function of myelin-forming Schwann cells. Similar to other tissues, the dystroglycan complex in Schwann cells localizes with different dystrophin family members in specific domains, thus promoting polarization. We show here that cleavage of dystroglycan by matrix metalloproteinases 2 and 9, an event that is considered pathological in most tissues, is finely and dynamically regulated in normal nerves and modulates dystroglycan complex composition and the size of Schwann cell compartments. In contrast, in nerves of Dy(2j/2j) mice, a model of laminin 211 deficiency, metalloproteinases 2 and 9 are increased, causing excessive dystroglycan cleavage and abnormal compartments. Pharmacological inhibition of cleavage rescues the cytoplasmic defects of Dy(2j/2j) Schwann cells. Thus, regulated cleavage may be a general mechanism to regulate protein complex composition in physiological conditions, whereas unregulated processing is pathogenic and a target for treatment in disease.


Subject(s)
Cell Compartmentation/physiology , Dystroglycans/metabolism , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Myelin Sheath/metabolism , Protein Interaction Domains and Motifs/physiology , Schwann Cells/metabolism , Animals , Cells, Cultured , Coculture Techniques , Disease Models, Animal , Dystroglycans/chemistry , Matrix Metalloproteinase 2/chemistry , Matrix Metalloproteinase 2/physiology , Matrix Metalloproteinase 9/chemistry , Matrix Metalloproteinase 9/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Myelin Sheath/enzymology , Nerve Fibers, Myelinated/metabolism , Nerve Fibers, Myelinated/pathology , Rats , Schwann Cells/enzymology , Sciatic Nerve/chemistry , Sciatic Nerve/metabolism , Sciatic Nerve/pathology
7.
J Neurosci ; 28(26): 6714-9, 2008 Jun 25.
Article in English | MEDLINE | ID: mdl-18579745

ABSTRACT

Schwann cells integrate signals deriving from the axon and the basal lamina to myelinate peripheral nerves. Integrin alpha6beta4 is a laminin receptor synthesized by Schwann cells and displayed apposed to the basal lamina. alpha6beta4 integrin expression in Schwann cells is induced by axons at the onset of myelination, and rises in adulthood. The beta4 chain has a uniquely long cytoplasmic domain that interacts with intermediate filaments such as dystonin, important in peripheral myelination. Furthermore, alpha6beta4 integrin binds peripheral myelin protein 22, whose alteration causes the most common demyelinating hereditary neuropathy. All these data suggest a role for alpha6beta4 integrin in peripheral nerve myelination. Here we show that ablating alpha6beta4 integrin specifically in Schwann cells of transgenic mice does not affect peripheral nerve development, myelin formation, maturation, or regeneration. However, consistent with maximal expression in adult nerves, alpha6beta4 integrin-null myelin is more prone to abnormal folding with aging. When the laminin receptor dystroglycan is also ablated, major folding abnormalities occur, associated with acute demyelination in some peripheral nervous system districts. These data indicate that, similar to its role in skin, alpha6beta4 integrin confers stability to myelin in peripheral nerves.


Subject(s)
Dystroglycans/metabolism , Integrin alpha6beta4/genetics , Integrin alpha6beta4/metabolism , Myelin Sheath/metabolism , Nerve Fibers, Myelinated/metabolism , Peripheral Nerves/metabolism , Aging/metabolism , Aging/pathology , Animals , Cell Differentiation/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Nerve Fibers, Myelinated/pathology , Peripheral Nerves/abnormalities , Peripheral Nerves/growth & development , Protein Folding , Schwann Cells/metabolism
8.
Neurobiol Dis ; 21(2): 314-23, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16199167

ABSTRACT

Twitcher (GALC(twi/twi)) is the murine model of globoid cell leukodystrophy (GLD or Krabbe disease), a disease caused by mutations of the lysosomal enzyme galactocerebrosidase (GALC). To verify the therapeutic potential on twitcher of neural stem/progenitor cells (NSPC), we transduced them with a GALC lentiviral vector. Brain injection of NSPC-GALC increased survival of GALC(twi/twi) from 36.1 +/- 4.1 to 52.2 +/- 5.6 days (P < 0.0001). Detection of GALC activity and flow cytometry showed that NSPC-GALC and NSPC expressing the green fluorescent protein were attracted to the posterior area of twitcher brain, where demyelination occurs first. GALC(twi/twi) microglia, also more abundant in posterior regions of the brain, released significant amounts of the cytotoxic cytokine TNF-alpha when matched with NSPC-GALC. Thus, in murine GLD, and possibly in other demyelinating diseases, NSPC are attracted to regions of active demyelination but have limited survival and therapeutic potential if attacked by activated macrophages/microglia.


Subject(s)
Leukodystrophy, Globoid Cell/therapy , Macrophage Activation/physiology , Macrophages/metabolism , Microglia/metabolism , Neurons/transplantation , Stem Cell Transplantation , Animals , Disease Models, Animal , Flow Cytometry , Galactosylceramidase/genetics , Galactosylceramidase/metabolism , Gene Transfer Techniques , Genetic Therapy/methods , Mice , Neurons/cytology , Transduction, Genetic
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