175 results on '"Feltri ML"'
Search Results
2. LRP1 Gene deletion in myelinating Schwann cells induces Schwann cell death and chronic neuropathic pain
- Author
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Campana, Wm, Mantuano, Elisabetta, Yamauchi, K, Yamauchi, T, De Corato, A, Feltri, Ml, Wrabetz, L, Gaultier, A, Gonias, Sl, and Henry, K.
- Published
- 2011
3. LRP1 Gene Deletion Links Myelinating Schwann Cell Survival to the Prevention of Chronic Neuropathic Pain
- Author
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Mantuano, Elisabetta, Henry, K, Yamauchi, K, Yamauchi, T, Gaultier, A, Feltri, Ml, Gonias, Sl, and Campana, Wm
- Published
- 2011
4. Expression of laminin receptors in schwann cell differentiation: evidence for distinct roles
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Previtali, S, Nodari, A, Taveggia, C, Pardini, C, Dina, G, Villa, A, Wrabetz, L, Quattrini, A, Feltri, M, Previtali, SC, Feltri, ML, VILLA, ANTONELLO, Previtali, S, Nodari, A, Taveggia, C, Pardini, C, Dina, G, Villa, A, Wrabetz, L, Quattrini, A, Feltri, M, Previtali, SC, Feltri, ML, and VILLA, ANTONELLO
- Abstract
Schwann cells require laminin-2 throughout nerve development, because mutations in the alpha2 chain in dystrophic mice interfere with sorting of axons before birth and formation of myelin internodes after birth. Mature Schwann cells express several laminin receptors, but their expression and roles in development are poorly understood. Therefore, we correlated the onset of myelination in nerve and synchronized myelinating cultures to the appearance of integrins and dystroglycan in Schwann cells. Only alpha6beta1 integrin is expressed before birth, whereas dystroglycan and alpha6beta4 integrin appear perinatally, just before myelination. Although dystroglycan is immediately polarized to the outer surface of Schwann cells, alpha6beta4 appears polarized only after myelination. We showed previously that Schwann cells lacking beta1 integrin do not relate properly to axons before birth. Here we show that the absence of beta1 before birth is not compensated by other laminin receptors, whereas coexpression of both dystroglycan and beta4 integrin is likely required for beta1-null Schwann cells to myelinate after birth. Finally, both beta1-null and dystrophic nerves contain bundles of unsorted axons, but they are predominant in different regions: in spinal roots in dystrophic mice and in nerves in beta1-null mice. We show that differential compensation by laminin-1, but not laminin receptors may partially explain this. These data suggest that the action of laminin is mediated by beta1 integrins during axonal sorting and by dystroglycan, alpha6beta1, and alpha6beta4 integrins during myelination.
- Published
- 2003
5. Epitope-tagged P-0 glycoprotein causes Charcot-Marie-Tooth-like neuropathy in transgenic mice
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Previtali, S, Quattrini, A, Fasolini, M, Panzeri, M, Villa, A, Filbin, M, Li, W, Chiu, S, Messing, A, Wrabetz, L, Feltri, M, Previtali, SC, Panzeri, MC, Filbin, MT, Li, WH, Chiu, SY, Feltri, ML, VILLA, ANTONELLO, Previtali, S, Quattrini, A, Fasolini, M, Panzeri, M, Villa, A, Filbin, M, Li, W, Chiu, S, Messing, A, Wrabetz, L, Feltri, M, Previtali, SC, Panzeri, MC, Filbin, MT, Li, WH, Chiu, SY, Feltri, ML, and VILLA, ANTONELLO
- Abstract
In peripheral nerve myelin, the intraperiod line results from compaction of the extracellular space due to homophilic adhesion between extracellular domains (ECD) of the protein zero (P-0) glycoprotein. Point mutations in this region of P-0 cause human hereditary demyelinating neuropathies such as Charcot-Marie-Tooth. We describe transgenic mice expressing a full-length P-0 modified in the ECD with a myc epitope tag. The presence of the myc sequence caused a dysmyelinating peripheral neuropathy similar to two distinct subtypes of Charcot-Marie-Tooth. with hypomyelination, altered intraperiod lines, and tomacula (thickened myelin). The tagged protein was incorporated into myelin and was associated with the morphological abnormalities. In vivo and in vitro experiments showed that P(0)myc retained partial adhesive function, and suggested that the transgene inhibits P-0-mediated adhesion in a dominant-negative fashion. These mice suggest new mechanisms underlying both the pathogenesis of P-0 ECD mutants and the normal interactions of P-0 in the myelin sheath.
- Published
- 2000
6. Unravelling the molecular basis of CMT4B pathology
- Author
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Bolis, A, primary, Previtali, S, additional, Bussini, S, additional, Dina, G, additional, Dati, G, additional, Feltri, ML, additional, Quattrini, A, additional, Wrabetz, L, additional, and Bolino, A, additional
- Published
- 2004
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7. Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 23
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Feltri, ML, primary, Saito, F, additional, Moore, SA, additional, Nodari, A, additional, Previtali, S, additional, Quattrini, A, additional, Messing, A, additional, Campbell, KP, additional, and Wrabetz, L, additional
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- 2003
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8. Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 34
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Previtali, SC, primary, Zerega, B, additional, Dina, G, additional, Dalcin, E, additional, Mustafa, AMS, additional, King, RHM, additional, Feltri, ML, additional, Wrabetz, L, additional, Quattrini, A, additional, and Bolino, A, additional
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- 2003
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9. Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 15
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Dati, G, primary, Quattrini, A, additional, Dina, G, additional, D’Antonio, M, additional, Fratta, P, additional, Messing, A, additional, Feltri, ML, additional, and Wrabetz, L, additional
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- 2003
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10. Conditional Disruption Of Beta 1 Integrin In Schwann Cells Impedes Interactions With Axons
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Feltri, ML, primary, Porta, DG, additional, Previtali, SC, additional, Nodari, A, additional, Migliavacca, B, additional, Cassetti, A, additional, Littlewood-Evans, A, additional, Reichardt, LF, additional, Messing, A, additional, Quattrini, A, additional, Mueller, U, additional, and Wrabetz, L., additional
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- 2002
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11. Morphological And Electrophysiological Signs Of Dysmyelination In Transgenic Mice Expressing CMT1B ( MPZ DELSer34 ) or DSS ( MPZ Ser34Cys ) Mutations
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Wrabetz, L, primary, D'Antonio, M, additional, Quattrini, A, additional, Dati, G, additional, Fratta, P, additional, Fasolini, M, additional, Zielasek, J, additional, Toyka, K, additional, Messing, A, additional, and Feltri, ML., additional
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- 2001
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12. αβ1 Integrins Are Required For Normal Peripheral Nerve Development
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Feltri, ML, primary, Quattrini, A, additional, Previtali, S, additional, Nodari, A, additional, Migliavacca, B, additional, Graus‐Porta, D, additional, Littlewood‐Evans, A, additional, Messing, A, additional, Mueller, U, additional, and Wrabetz, L., additional
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- 2001
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13. Toward a transgenic mouse model of remyelination
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Ferraresi, S., primary, Lorenzetti, I., additional, Nemni, R., additional, Kamholz, J., additional, Feltri, ML, additional, and Wrabetz, L., additional
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- 1997
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14. Curcumin derivatives promote Schwann cell differentiation and improve neuropathy in R98C CMT1B mice.
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Patzkó A, Bai Y, Saporta MA, Katona I, Wu X, Vizzuso D, Feltri ML, Wang S, Dillon LM, Kamholz J, Kirschner D, Sarkar FH, Wrabetz L, Shy ME, Patzkó, Agnes, Bai, Yunhong, Saporta, Mario A, Katona, István, Wu, Xingyao, and Vizzuso, Domenica
- Abstract
Charcot-Marie-Tooth disease type 1B is caused by mutations in myelin protein zero. R98C mice, an authentic model of early onset Charcot-Marie-Tooth disease type 1B, develop neuropathy in part because the misfolded mutant myelin protein zero is retained in the endoplasmic reticulum where it activates the unfolded protein response. Because oral curcumin, a component of the spice turmeric, has been shown to relieve endoplasmic reticulum stress and decrease the activation of the unfolded protein response, we treated R98C mutant mice with daily gastric lavage of curcumin or curcumin derivatives starting at 4 days of age and analysed them for clinical disability, electrophysiological parameters and peripheral nerve morphology. Heterozygous R98C mice treated with curcumin dissolved in sesame oil or phosphatidylcholine curcumin performed as well as wild-type littermates on a rotarod test and had increased numbers of large-diameter axons in their sciatic nerves. Treatment with the latter two compounds also increased compound muscle action potential amplitudes and the innervation of neuromuscular junctions in both heterozygous and homozygous R98C animals, but it did not improve nerve conduction velocity, myelin thickness, G-ratios or myelin period. The expression of c-Jun and suppressed cAMP-inducible POU (SCIP)-transcription factors that inhibit myelination when overexpressed-was also decreased by treatment. Consistent with its role in reducing endoplasmic reticulum stress, treatment with curcumin dissolved in sesame oil or phosphatidylcholine curcumin was associated with decreased X-box binding protein (XBP1) splicing. Taken together, these data demonstrate that treatment with curcumin dissolved in sesame oil or phosphatidylcholine curcumin improves the peripheral neuropathy of R98C mice by alleviating endoplasmic reticulum stress, by reducing the activation of unfolded protein response and by promoting Schwann cell differentiation. [ABSTRACT FROM AUTHOR]
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- 2012
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15. MpzR98C arrests Schwann cell development in a mouse model of early-onset Charcot-Marie-Tooth disease type 1B.
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Saporta MA, Shy BR, Patzko A, Bai Y, Pennuto M, Ferri C, Tinelli E, Saveri P, Kirschner D, Crowther M, Southwood C, Wu X, Gow A, Feltri ML, Wrabetz L, Shy ME, Saporta, Mario A C, Shy, Brian R, Patzko, Agnes, and Bai, Yunhong
- Abstract
Mutations in myelin protein zero (MPZ) cause Charcot-Marie-Tooth disease type 1B. Many dominant MPZ mutations, including R98C, present as infantile onset dysmyelinating neuropathies. We have generated an R98C 'knock-in' mouse model of Charcot-Marie-Tooth type 1B, where a mutation encoding R98C was targeted to the mouse Mpz gene. Both heterozygous (R98C/+) and homozygous (R98C/R98C) mice develop weakness, abnormal nerve conduction velocities and morphologically abnormal myelin; R98C/R98C mice are more severely affected. MpzR98C is retained in the endoplasmic reticulum of Schwann cells and provokes a transitory, canonical unfolded protein response. Ablation of Chop, a mediator of the protein kinase RNA-like endoplasmic reticulum kinase unfolded protein response pathway restores compound muscle action potential amplitudes of R98C/+ mice but does not alter the reduced conduction velocities, reduced axonal diameters or clinical behaviour of these animals. R98C/R98C Schwann cells are developmentally arrested in the promyelinating stage, whereas development is delayed in R98C/+ mice. The proportion of cells expressing c-Jun, an inhibitor of myelination, is elevated in mutant nerves, whereas the proportion of cells expressing the promyelinating transcription factor Krox-20 is decreased, particularly in R98C/R98C mice. Our results provide a potential link between the accumulation of MpzR98C in the endoplasmic reticulum and a developmental delay in myelination. These mice provide a model by which we can begin to understand the early onset dysmyelination seen in patients with R98C and similar mutations. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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16. Foot pad skin biopsy in mouse models of hereditary neuropathy
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Maria Laura Feltri, Angelo Quattrini, Ignazio Diego Lopez, Alessandra Bolino, Stefano C. Previtali, Lawrence Wrabetz, Giuseppe Lauria, Federica Cerri, Giancarlo Comi, Patrizia Dacci, Giorgia Dina, Dacci, P, Dina, G, Cerri, F, Previtali, Sc, Lopez, Id, Lauria, G, Feltri, Ml, Bolino, A, Comi, Giancarlo, Wrabetz, L, and Quattrini, A.
- Subjects
Biopsy ,Sural nerve ,Nerve Fibers, Myelinated ,dermal nerve ,epidermal nerve ,Cellular and Molecular Neuroscience ,Myelin ,Mice ,Mice, Neurologic Mutants ,Sural Nerve ,Charcot-Marie-Tooth Disease ,medicine ,Animals ,Humans ,Myelin Sheath ,medicine.diagnostic_test ,business.industry ,Foot ,CMT ,Anatomy ,Dermis ,medicine.disease ,Sciatic Nerve ,Axons ,Disease Models, Animal ,medicine.anatomical_structure ,Neurology ,nervous system ,Peripheral nervous system ,Knockout mouse ,Skin biopsy ,Congenital muscular dystrophy ,Sciatic nerve ,Epidermis ,business ,Research Article - Abstract
Numerous transgenic and knockout mouse models of human hereditary neuropathies have become available over the past decade. We describe a simple, reproducible, and safe biopsy of mouse skin for histopathological evaluation of the peripheral nervous system (PNS) in models of hereditary neuropathies. We compared the diagnostic outcome between sciatic nerve and dermal nerves found in skin biopsy (SB) from the hind foot. A total of five animal models of different Charcot-Marie-Tooth neuropathies, and one model of congenital muscular dystrophy associated neuropathy were examined. In wild type mice, dermal nerve fibers were readily identified by immunohistochemistry, light, and electron microscopy and they appeared similar to myelinated fibers in sciatic nerve. In mutant mice, SB manifested myelin abnormalities similar to those observed in sciatic nerves, including hypomyelination, onion bulbs, myelin outfolding, redundant loops, and tomacula. In many strains, however, SB showed additional abnormalities—fiber loss, dense neurofilament packing with lower phosphorylation status, and axonal degeneration—undetected in sciatic nerve, possibly because SB samples distal nerves. SB, a reliable technique to investigate peripheral neuropathies in human beings, is also useful to investigate animal models of hereditary neuropathies. Our data indicate that SB may reveal distal axonal pathology in mouse models and permits sequential follow-up of the neuropathy in an individual mouse, thereby reducing the number of mice necessary to document pathology of the PNS. © 2010 Wiley-Liss, Inc.
- Published
- 2010
17. Jab1 regulates Schwann cell proliferation and axonal sorting through p27
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Cristina Rivellini, Daniela Triolo, Stefano C. Previtali, Maria Laura Feltri, Angelo Quattrini, Giorgia Dina, Ruggero Pardi, Emanuela Porrello, Daniela Ungaro, Lawrence Wrabetz, Ubaldo Del Carro, Martina Panattoni, Porrello, E, Rivellini, C, Dina, G, Triolo, D, Del Carro, U, Ungaro, D, Panattoni, M, Feltri, Ml, Wrabetz, L, Pardi, Ruggero, Quattrini, A, and Previtali, S. C.
- Subjects
Cellular differentiation ,Neurogenesis ,Immunology ,Blotting, Western ,Schwann cell ,Article ,Schwann cell proliferation ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Laminin ,medicine ,In Situ Nick-End Labeling ,Immunology and Allergy ,Animals ,Body Weights and Measures ,Neuregulin 1 ,Of Interest ,Cell Proliferation ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,biology ,Cell growth ,COP9 Signalosome Complex ,Intracellular Signaling Peptides and Proteins ,Cell Differentiation ,From J. Exp. Med ,Cell Biology ,Cell cycle ,Immunohistochemistry ,Axons ,Cell biology ,medicine.anatomical_structure ,nervous system ,Bromodeoxyuridine ,Rotarod Performance Test ,biology.protein ,Schwann Cells ,030217 neurology & neurosurgery ,Cyclin-Dependent Kinase Inhibitor p27 ,Peptide Hydrolases ,030215 immunology - Abstract
Jab1 constitutes a regulatory molecule that integrates laminin211 signals in Schwann cells to govern cell cycle, cell number, and differentiation., Axonal sorting is a crucial event in nerve formation and requires proper Schwann cell proliferation, differentiation, and contact with axons. Any defect in axonal sorting results in dysmyelinating peripheral neuropathies. Evidence from mouse models shows that axonal sorting is regulated by laminin211– and, possibly, neuregulin 1 (Nrg1)–derived signals. However, how these signals are integrated in Schwann cells is largely unknown. We now report that the nuclear Jun activation domain–binding protein 1 (Jab1) may transduce laminin211 signals to regulate Schwann cell number and differentiation during axonal sorting. Mice with inactivation of Jab1 in Schwann cells develop a dysmyelinating neuropathy with axonal sorting defects. Loss of Jab1 increases p27 levels in Schwann cells, which causes defective cell cycle progression and aberrant differentiation. Genetic down-regulation of p27 levels in Jab1-null mice restores Schwann cell number, differentiation, and axonal sorting and rescues the dysmyelinating neuropathy. Thus, Jab1 constitutes a regulatory molecule that integrates laminin211 signals in Schwann cells to govern cell cycle, cell number, and differentiation. Finally, Jab1 may constitute a key molecule in the pathogenesis of dysmyelinating neuropathies.
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- 2013
18. Schwann Cell Development and Myelination.
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Salzer J, Feltri ML, and Jacob C
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- Animals, Humans, Signal Transduction, Peripheral Nervous System, Extracellular Matrix metabolism, Cell Differentiation, Schwann Cells metabolism, Schwann Cells physiology, Myelin Sheath metabolism, Myelin Sheath physiology, Axons physiology, Axons metabolism
- Abstract
Glial cells in the peripheral nervous system (PNS), which arise from the neural crest, include axon-associated Schwann cells (SCs) in nerves, synapse-associated SCs at the neuromuscular junction, enteric glia, perikaryon-associated satellite cells in ganglia, and boundary cap cells at the border between the central nervous system (CNS) and the PNS. Here, we focus on axon-associated SCs. These SCs progress through a series of formative stages, which culminate in the generation of myelinating SCs that wrap large-caliber axons and of nonmyelinating (Remak) SCs that enclose multiple, small-caliber axons. In this work, we describe SC development, extrinsic signals from the axon and extracellular matrix (ECM) and the intracellular signaling pathways they activate that regulate SC development, and the morphogenesis and organization of myelinating SCs and the myelin sheath. We review the impact of SCs on the biology and integrity of axons and their emerging role in regulating peripheral nerve architecture. Finally, we explain how transcription and epigenetic factors control and fine-tune SC development and myelination., (Copyright © 2024 Cold Spring Harbor Laboratory Press; all rights reserved.)
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- 2024
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19. Loss of prohibitin 2 in Schwann cells dysregulates key transcription factors controlling developmental myelination.
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Wilson ER, Nunes GD, Shen S, Moore S, Gawron J, Maxwell J, Syed U, Hurley E, Lanka M, Qu J, Désaubry L, Wrabetz L, Poitelon Y, and Feltri ML
- Abstract
Schwann cells are critical for the proper development and function of the peripheral nervous system (PNS), where they form a collaborative relationship with axons. Past studies highlighted that a pair of proteins called the prohibitins play major roles in Schwann cell biology. Prohibitins are ubiquitously expressed and versatile proteins. We have previously shown that while prohibitins play a crucial role in Schwann cell mitochondria for long-term myelin maintenance and axon health, they may also be present at the Schwann cell-axon interface during development. Here, we expand on this, showing that drug-mediated modulation of prohibitins in vitro disrupts myelination and confirming that Schwann cell-specific ablation of prohibitin 2 (Phb2) in vivo results in severe defects in radial sorting and myelination. We show in vivo that Phb2-null Schwann cells cannot effectively proliferate and the transcription factors EGR2 (KROX20), POU3F1 (OCT6), and POU3F2 (BRN2), necessary for proper Schwann cell maturation, are dysregulated. Schwann cell-specific deletion of Jun, a transcription factor associated with negative regulation of myelination, confers partial rescue of the developmental defect seen in mice lacking Schwann cell Phb2. Finally, we identify a pool of candidate PHB2 interactors that change their interaction with PHB2 depending on neuronal signals, and thus are potential mediators of PHB2-associated developmental defects. This work develops our understanding of Schwann cell biology, revealing that Phb2 may modulate the timely expression of transcription factors necessary for proper PNS development, and proposing candidates that may play a role in PHB2-mediated integration of axon signals in the Schwann cell., (© 2024 Wiley Periodicals LLC.)
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- 2024
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20. Human iPSC-derived myelinating organoids and globoid cells to study Krabbe Disease.
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Evans LMP, Gawron J, Sim FJ, Feltri ML, and Marziali LN
- Abstract
Krabbe disease (Kd) is a lysosomal storage disorder (LSD) caused by the deficiency of the lysosomal galactosylceramidase (GALC) which cleaves the myelin enriched lipid galactosylceramide (GalCer). Accumulated GalCer is catabolized into the cytotoxic lipid psychosine that causes myelinating cells death and demyelination which recruits microglia/macrophages that fail to digest myelin debris and become globoid cells. Here, to understand the pathological mechanisms of Kd, we used induced pluripotent stem cells (iPSCs) from Kd patients to produce myelinating organoids and microglia. We show that Kd organoids have no obvious defects in neurogenesis, astrogenesis, and oligodendrogenesis but manifest early myelination defects. Specifically, Kd organoids showed shorter but a similar number of myelin internodes than Controls at the peak of myelination and a reduced number and shorter internodes at a later time point. Interestingly, myelin is affected in the absence of autophagy and mTOR pathway dysregulation, suggesting lack of lysosomal dysfunction which makes this organoid model a very valuable tool to study the early events that drive demyelination in Kd. Kd iPSC-derived microglia show a marginal rate of globoid cell formation under normal culture conditions that is drastically increased upon GalCer feeding. Under normal culture conditions, Kd microglia show a minor LAMP1 content decrease and a slight increase in the autophagy protein LC3B. Upon GalCer feeding, Kd cells show accumulation of autophagy proteins and strong LAMP1 reduction that at a later time point are reverted showing the compensatory capabilities of globoid cells. Altogether, this supports the value of our cultures as tools to study the mechanisms that drive globoid cell formation and the compensatory mechanism in play to overcome GalCer accumulation in Kd.
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- 2024
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21. Loss of YAP in Schwann cells improves HNPP pathophysiology.
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Moore SM, Jeong E, Zahid M, Gawron J, Arora S, Belin S, Sim F, Poitelon Y, and Feltri ML
- Abstract
Rapid nerve conduction in the peripheral nervous system (PNS) is facilitated by the multilamellar myelin sheath encasing many axons of peripheral nerves. Charcot-Marie-Tooth type 1A (CMT1A), and hereditary neuropathy with liability to pressure palsy (HNPP) are common demyelinating inherited peripheral neuropathies and are caused by mutations in the peripheral myelin protein 22 (PMP22) gene. Duplication of PMP22 leads to its overexpression and causes CMT1A, while its deletion results in PMP22 under expression and causes HNPP. Here, we investigated novel targets for modulating the protein level of PMP22 in HNPP. We found that genetic attenuation of the transcriptional coactivator Yap in Schwann cells reduces p-TAZ levels, increased TAZ activity, and increases PMP22 in peripheral nerves. Based on these findings, we ablated Yap alleles in Schwann cells of the Pmp22-haploinsufficient mouse model of HNPP and identified fewer tomacula on morphological assessment and improved nerve conduction in peripheral nerves. These findings suggest YAP modulation may be a new avenue for treatment of HNPP., (© 2024 Wiley Periodicals LLC.)
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- 2024
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22. p38γ MAPK delays myelination and remyelination and is abundant in multiple sclerosis lesions.
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Marziali LN, Hwang Y, Palmisano M, Cuenda A, Sim FJ, Gonzalez A, Volsko C, Dutta R, Trapp BD, Wrabetz L, and Feltri ML
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- Animals, Mice, Humans, Mitogen-Activated Protein Kinase 12 metabolism, Mitogen-Activated Protein Kinase 12 genetics, Cell Differentiation physiology, Cuprizone toxicity, Mice, Inbred C57BL, Male, Female, Demyelinating Diseases pathology, Demyelinating Diseases metabolism, Oligodendrocyte Precursor Cells metabolism, Oligodendrocyte Precursor Cells pathology, Mice, Transgenic, Remyelination physiology, Multiple Sclerosis pathology, Multiple Sclerosis metabolism, Myelin Sheath metabolism, Myelin Sheath pathology, Oligodendroglia metabolism, Oligodendroglia pathology
- Abstract
Multiple sclerosis is a chronic inflammatory disease in which disability results from the disruption of myelin and axons. During the initial stages of the disease, injured myelin is replaced by mature myelinating oligodendrocytes that differentiate from oligodendrocyte precursor cells. However, myelin repair fails in secondary and chronic progressive stages of the disease and with ageing, as the environment becomes progressively more hostile. This may be attributable to inhibitory molecules in the multiple sclerosis environment including activation of the p38MAPK family of kinases. We explored oligodendrocyte precursor cell differentiation and myelin repair using animals with conditional ablation of p38MAPKγ from oligodendrocyte precursors. We found that p38γMAPK ablation accelerated oligodendrocyte precursor cell differentiation and myelination. This resulted in an increase in both the total number of oligodendrocytes and the migration of progenitors ex vivo and faster remyelination in the cuprizone model of demyelination/remyelination. Consistent with its role as an inhibitor of myelination, p38γMAPK was significantly downregulated as oligodendrocyte precursor cells matured into oligodendrocytes. Notably, p38γMAPK was enriched in multiple sclerosis lesions from patients. Oligodendrocyte progenitors expressed high levels of p38γMAPK in areas of failed remyelination but did not express detectable levels of p38γMAPK in areas where remyelination was apparent. Our data suggest that p38γ could be targeted to improve myelin repair in multiple sclerosis., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2024
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23. Knockout of PA200 improves proteasomal degradation and myelination in a proteotoxic neuropathy.
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VerPlank JJ, Gawron JM, Silvestri NJ, Wrabetz L, and Feltri ML
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- Animals, Mice, Cytoplasm metabolism, Mice, Knockout, Proteolysis, Charcot-Marie-Tooth Disease genetics, Proteasome Endopeptidase Complex metabolism, Nuclear Proteins metabolism
- Abstract
The cellular response to a decrease in protein degradation by 26S proteasomes in chronic diseases is poorly understood. Pharmacological inhibition of proteasomes increases the expression of proteasome subunits and Proteasome Activator 200 (PA200), an alternative proteasome activator. In the S63del mouse model of the peripheral neuropathy Charcot Marie Tooth 1B (CMT1B), proteasomal protein degradation is decreased and proteasome gene expression is increased. Here, we show an increase in PA200 and PA200-bound proteasomes in the peripheral nerves of S63del mice. To test genetically whether the upregulation of PA200 was compensatory, we generated S63del//PA200-/- mice. Unexpectedly, in the sciatic nerves of these mice, there was greater proteasomal protein degradation than in S63del, less polyubiquitinated proteins and markers of the unfolded protein response, and a greater amount of assembled, active 26S proteasomes. These changes were not seen in PA200-/- controls and were therefore specific to the neuropathy. Furthermore, in S63del//PA200-/- mice, myelin thickness and nerve conduction were restored to WT levels. Thus, the upregulation of PA200 is maladaptive in S63del mice and its genetic ablation prevented neuropathy., (© 2024 VerPlank et al.)
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- 2024
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24. YAP and TAZ regulate remyelination in the central nervous system.
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Hong J, Kirkland JM, Acheta J, Marziali LN, Beck B, Jeanette H, Bhatia U, Davis G, Herron J, Roué C, Abi-Ghanem C, Feltri ML, Zuloaga KL, Bechler ME, Poitelon Y, and Belin S
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- Animals, Central Nervous System physiology, Myelin Sheath metabolism, Schwann Cells metabolism, Oligodendroglia metabolism, Remyelination
- Abstract
Myelinating cells are sensitive to mechanical stimuli from their extracellular matrix. Ablation of YAP and TAZ mechanotransducers in Schwann cells abolishes the axon-Schwann cell recognition, myelination, and remyelination in the peripheral nervous system. It was unknown if YAP and TAZ are also required for myelination and remyelination in the central nervous system. Here we define the importance of oligodendrocyte (OL) YAP and TAZ in vivo, by specific deletion in oligodendroglial cells in adult OLs during myelin repair. Blocking YAP and TAZ expression in OL lineage cells did not affect animal viability or any major defects on OL maturation and myelination. However, using a mouse model of demyelination/remyelination, we demonstrate that YAP and TAZ modulate the capacity of OLs to remyelinate axons, particularly during the early stage of the repair process, when OL proliferation is most important. These results indicate that YAP and TAZ signaling is necessary for effective remyelination of the mouse brain., (© 2023 The Authors. GLIA published by Wiley Periodicals LLC.)
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- 2024
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25. Aryl hydrocarbon receptor is a tumor promoter in MYCN -amplified neuroblastoma cells through suppression of differentiation.
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Chaudhry KA, Jacobi JJ, Gillard BM, Karasik E, Martin JC, da Silva Fernandes T, Hurley E, Feltri ML, Attwood KM, Twist CJ, Smiraglia DJ, Long MD, and Bianchi-Smiraglia A
- Abstract
Neuroblastoma is the most common extracranial solid tumor in children. MYCN amplification is detected in almost half of high-risk cases and is associated with poorly differentiated tumors, poor patient prognosis and poor response to therapy, including retinoids. We identify the aryl hydrocarbon receptor (AhR) as a transcription factor promoting the growth and suppressing the differentiation of MYCN -amplified neuroblastoma. A neuroblastoma specific AhR transcriptional signature reveals an inverse correlation of AhR activity with patients' outcome, suggesting AhR activity is critical for disease progression. AhR modulates chromatin structures, reducing accessibility to regions responsive to retinoic acid. Genetic and pharmacological inhibition of AhR results in induction of differentiation. Importantly, AhR antagonism with clofazimine synergizes with retinoic acid in inducing differentiation both in vitro and in vivo . Thus, we propose AhR as a target for MYCN -amplified neuroblastoma and that its antagonism, combined with current standard-of-care, may result in a more durable response in patients., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)
- Published
- 2023
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26. Lithium's effects on therapeutic targets and MRI biomarkers in Parkinson's disease: A pilot clinical trial.
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Guttuso T Jr, Shepherd R, Frick L, Feltri ML, Frerichs V, Ramanathan M, Zivadinov R, and Bergsland N
- Abstract
Background: Lithium has a wide range of neuroprotective actions, has been effective in Parkinson's disease (PD) animal models and may account for the decreased risk of PD in smokers., Methods: This open-label pilot clinical trial randomized 16 PD patients to "high-dose" ( n = 5, lithium carbonate titrated to achieve serum level of 0.4-0.5 mmol/L), "medium-dose" ( n = 6, 45 mg/day lithium aspartate) or "low-dose" ( n = 5, 15 mg/day lithium aspartate) lithium therapy for 24-weeks. Peripheral blood mononuclear cell (PBMC) mRNA expression of nuclear receptor-related-1 (Nurr1) and superoxide dismutase-1 (SOD1) were assessed by qPCR in addition to other PD therapeutic targets. Two patients from each group received multi-shell diffusion MRI scans to assess for free water (FW) changes in the dorsomedial nucleus of the thalamus and nucleus basalis of Meynert, which reflect cognitive decline in PD, and the posterior substantia nigra, which reflects motor decline in PD., Results: Two of the six patients receiving medium-dose lithium therapy withdrew due to side effects. Medium-dose lithium therapy was associated with the greatest numerical increases in PBMC Nurr1 and SOD1 expression (679% and 127%, respectively). Also, medium-dose lithium therapy was the only dosage associated with mean numerical decreases in brain FW in all three regions of interest, which is the opposite of the known longitudinal FW changes in PD., Conclusion: Medium-dose lithium aspartate therapy was associated with engagement of blood-based therapeutic targets and improvements in MRI disease-progression biomarkers but was poorly tolerated in 33% of patients. Further PD clinical research is merited examining lithium's tolerability, effects on biomarkers and potential disease-modifying effects., Competing Interests: Authors’ Conflicts of Interest for previous 12 months: Thomas Guttuso, Jr.: President of e3 Pharmaceuticals, Inc. Support from UCB for clinical trial patient enrollment. Rachel Shepherd: None. Luciana Frick: None. Laura Feltri: None. Valerie Frerichs: None. Murali Ramanathan: None. Robert Zivadinov: Received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Novartis, Sanofi, 415 Capital, Mapi Pharma and Janssen for speaking and consultant fees. He received financial support for research activities from Bristol Myers Squibb, Sanofi, Novartis, EMDSerono, V-WAVE Medical, Mapi Pharma, CorEvitas and Protembis. Niels Bergsland: None., (© 2023 The Authors.)
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- 2023
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27. Cholinergic neurons in the basal forebrain are involved in behavioral abnormalities associated with Cul3 deficiency: Role of prefrontal cortex projections in cognitive deficits.
- Author
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Rapanelli M, Wang W, Hurley E, Feltri ML, Pittenger C, Frick LR, and Yan Z
- Subjects
- Animals, Mice, Cholinergic Agents, Cognition physiology, Choline O-Acetyltransferase genetics, Choline O-Acetyltransferase metabolism, Basal Forebrain metabolism, Cholinergic Neurons metabolism, Cognitive Dysfunction genetics, Cognitive Dysfunction metabolism, Cullin Proteins genetics, Cullin Proteins metabolism, Prefrontal Cortex metabolism
- Abstract
Loss-of-function mutations of the gene Cul3 have been identified as a risk factor for autism-spectrum disorder (ASD), but the pathogenic mechanisms are not well understood. Conditional Cul3 ablation in cholinergic neurons of mice (Chat
CRE Cul3F/+ ) recapitulated ASD-like social and sensory gating phenotypes and caused significant cognitive impairments, with diminished activity of cholinergic neurons in the basal forebrain (BF). Chemogenetic inhibition of BF cholinergic neurons in healthy mice induced similar social and cognitive deficits. Conversely, chemogenetic stimulation of BF cholinergic neurons in ChatCRE Cul3F/+ mice reversed abnormalities in sensory gating and cognition. Cortical hypofunction was also found after ChAT-specific Cul3 ablation and stimulation of cholinergic projections from the BF to the prefrontal cortex (PFC) mitigated cognitive deficits. Overall, we demonstrate that cholinergic dysfunction due to Cul3 deficiency is involved in ASD-like behavioral abnormalities, and that BF cholinergic neurons are particularly critical for cognitive component through their projections to the PFC., (© 2023. The Author(s).)- Published
- 2023
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28. A new mouse model of Charcot-Marie-Tooth 2J neuropathy replicates human axonopathy and suggest alteration in axo-glia communication.
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Shackleford G, Marziali LN, Sasaki Y, Claessens A, Ferri C, Weinstock NI, Rossor AM, Silvestri NJ, Wilson ER, Hurley E, Kidd GJ, Manohar S, Ding D, Salvi RJ, Feltri ML, D'Antonio M, and Wrabetz L
- Subjects
- Humans, Mice, Animals, Myelin Sheath genetics, Myelin Sheath metabolism, Axons metabolism, Neuroglia, Mice, Knockout, Disease Models, Animal, Communication, Charcot-Marie-Tooth Disease genetics
- Abstract
Myelin is essential for rapid nerve impulse propagation and axon protection. Accordingly, defects in myelination or myelin maintenance lead to secondary axonal damage and subsequent degeneration. Studies utilizing genetic (CNPase-, MAG-, and PLP-null mice) and naturally occurring neuropathy models suggest that myelinating glia also support axons independently from myelin. Myelin protein zero (MPZ or P0), which is expressed only by Schwann cells, is critical for myelin formation and maintenance in the peripheral nervous system. Many mutations in MPZ are associated with demyelinating neuropathies (Charcot-Marie-Tooth disease type 1B [CMT1B]). Surprisingly, the substitution of threonine by methionine at position 124 of P0 (P0T124M) causes axonal neuropathy (CMT2J) with little to no myelin damage. This disease provides an excellent paradigm to understand how myelinating glia support axons independently from myelin. To study this, we generated targeted knock-in MpzT124M mutant mice, a genetically authentic model of T124M-CMT2J neuropathy. Similar to patients, these mice develop axonopathy between 2 and 12 months of age, characterized by impaired motor performance, normal nerve conduction velocities but reduced compound motor action potential amplitudes, and axonal damage with only minor compact myelin modifications. Mechanistically, we detected metabolic changes that could lead to axonal degeneration, and prominent alterations in non-compact myelin domains such as paranodes, Schmidt-Lanterman incisures, and gap junctions, implicated in Schwann cell-axon communication and axonal metabolic support. Finally, we document perturbed mitochondrial size and distribution along MpzT124M axons suggesting altered axonal transport. Our data suggest that Schwann cells in P0T124M mutant mice cannot provide axons with sufficient trophic support, leading to reduced ATP biosynthesis and axonopathy. In conclusion, the MpzT124M mouse model faithfully reproduces the human neuropathy and represents a unique tool for identifying the molecular basis for glial support of axons., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Shackleford et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2022
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29. Peripheral glia diversity.
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Reed CB, Feltri ML, and Wilson ER
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- Astrocytes, Central Nervous System, Peripheral Nerves, Neuroglia, Schwann Cells
- Abstract
Recent years have seen an evolving appreciation for the role of glial cells in the nervous system. As we move away from the typical neurocentric view of neuroscience, the complexity and variability of central nervous system glia is emerging, far beyond the three main subtypes: astrocytes, oligodendrocytes, and microglia. Yet the diversity of the glia found in the peripheral nervous system remains rarely discussed. In this review, we discuss the developmental origin, morphology, and function of the different populations of glia found in the peripheral nervous system, including: myelinating Schwann cells, Remak Schwann cells, repair Schwann cells, satellite glia, boundary cap-derived glia, perineurial glia, terminal Schwann cells, glia found in the skin, olfactory ensheathing cells, and enteric glia. The morphological and functional heterogeneity of glia found in the periphery reflects the diverse roles the nervous system performs throughout the body. Further, it highlights a complexity that should be appreciated and considered when it comes to a complete understanding of the peripheral nervous system in health and disease., (© 2021 Anatomical Society.)
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- 2022
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30. Beyond Wrapping: Canonical and Noncanonical Functions of Schwann Cells.
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Taveggia C and Feltri ML
- Subjects
- Axons metabolism, Central Nervous System physiology, Neuroglia physiology, Peripheral Nervous System physiology, Schwann Cells metabolism
- Abstract
Schwann cells in the peripheral nervous system (PNS) are essential for the support and myelination of axons, ensuring fast and accurate communication between the central nervous system and the periphery. Schwann cells and related glia accompany innervating axons in virtually all tissues in the body, where they exhibit remarkable plasticity and the ability to modulate pathology in extraordinary, and sometimes surprising, ways. Here, we provide a brief overview of the various glial cell types in the PNS and describe the cornerstone cellular and molecular processes that enable Schwann cells to perform their canonical functions. We then dive into discussing exciting noncanonical functions of Schwann cells and related PNS glia, which include their role in organizing the PNS, in regulating synaptic activity and pain, in modulating immunity, in providing a pool of stem cells for different organs, and, finally, in influencing cancer.
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- 2022
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31. Neuron-specific ablation of the Krabbe disease gene galactosylceramidase in mice results in neurodegeneration.
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Kreher C, Favret J, Weinstock NI, Maulik M, Hong X, Gelb MH, Wrabetz L, Feltri ML, and Shin D
- Subjects
- Animals, Disease Models, Animal, Mice, Neurons pathology, Psychosine, Galactosylceramidase genetics, Leukodystrophy, Globoid Cell genetics, Leukodystrophy, Globoid Cell pathology
- Abstract
Krabbe disease is caused by a deficiency of the lysosomal galactosylceramidase (GALC) enzyme, which results in the accumulation of galactosylceramide (GalCer) and psychosine. In Krabbe disease, the brunt of demyelination and neurodegeneration is believed to result from the dysfunction of myelinating glia. Recent studies have shown that neuronal axons are both structurally and functionally compromised in Krabbe disease, even before demyelination, suggesting a possible neuron-autonomous role of GALC. Using a novel neuron-specific Galc knockout (CKO) model, we show that neuronal Galc deletion is sufficient to cause growth and motor coordination defects and inflammatory gliosis in mice. Furthermore, psychosine accumulates significantly in the nervous system of neuron-specific Galc-CKO. Confocal and electron microscopic analyses show profound neuro-axonal degeneration with a mild effect on myelin structure. Thus, we prove for the first time that neuronal GALC is essential to maintain and protect neuronal function independently of myelin and may directly contribute to the pathogenesis of Krabbe disease., Competing Interests: The authors have declared that no competing interests exist.
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- 2022
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32. Phosphorylation of guanosine monophosphate reductase triggers a GTP-dependent switch from pro- to anti-oncogenic function of EPHA4.
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Wolff DW, Deng Z, Bianchi-Smiraglia A, Foley CE, Han Z, Wang X, Shen S, Rosenberg MM, Moparthy S, Yun DH, Chen J, Baker BK, Roll MV, Magiera AJ, Li J, Hurley E, Feltri ML, Cox AO, Lee J, Furdui CM, Liu L, Bshara W, LaConte LEW, Kandel ES, Pasquale EB, Qu J, Hedstrom L, and Nikiforov MA
- Subjects
- GMP Reductase genetics, GMP Reductase metabolism, Guanosine Triphosphate metabolism, Humans, Nucleotides metabolism, Phosphorylation, Melanoma metabolism, Receptor, EphA4 metabolism
- Abstract
Signal transduction pathways post-translationally regulating nucleotide metabolism remain largely unknown. Guanosine monophosphate reductase (GMPR) is a nucleotide metabolism enzyme that decreases GTP pools by converting GMP to IMP. We observed that phosphorylation of GMPR at Tyr267 is critical for its activity and found that this phosphorylation by ephrin receptor tyrosine kinase EPHA4 decreases GTP pools in cell protrusions and levels of GTP-bound RAC1. EPHs possess oncogenic and tumor-suppressor activities, although the mechanisms underlying switches between these two modes are poorly understood. We demonstrated that GMPR plays a key role in EPHA4-mediated RAC1 suppression. This supersedes GMPR-independent activation of RAC1 by EPHA4, resulting in a negative overall effect on melanoma cell invasion and tumorigenicity. Accordingly, EPHA4 levels increase during melanoma progression and inversely correlate with GMPR levels in individual melanoma tumors. Therefore, phosphorylation of GMPR at Tyr267 is a metabolic signal transduction switch controlling GTP biosynthesis and transformed phenotypes., Competing Interests: Declaration of interests The authors declare no competing financial interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2022
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33. Cc2d1b Contributes to the Regulation of Developmental Myelination in the Central Nervous System.
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Acheta J, Hong J, Jeanette H, Brar S, Yalamanchili A, Feltri ML, Manzini MC, Belin S, and Poitelon Y
- Abstract
Background: Numerous studies have indicated that myelination is the result of the interplay between extracellular signals and an intricate network of transcription factors. Yet, the identification and characterization of the full repertoire of transcription factors that modulate myelination are still incomplete. CC2D1B is a member of the Lgd/CC2D1 family of proteins highly expressed in myelinating cells in the central and peripheral nervous systems. In addition, the absence of CC2D1B limits myelin formation in vitro . Here we propose to delineate the function of CC2D1B in myelinating cells during developmental myelination in vivo in the central and peripheral nervous systems., Methods: We used a Cc2d1b constitutive knockout mouse model and then performed morphological analyses on semithin sections of sciatic nerves and electron micrographs of optic nerves. We also performed immunohistological studies on coronal brain sections. All analyses were performed at 30 days of age., Results: In the peripheral nervous system, animals ablated for Cc2d1b did not show any myelin thickness difference compared to control animals. In the central nervous system, immunohistological studies did not show any difference in the number of oligodendrocytes or the level of myelin proteins in the cortex, corpus callosum, and striatum. However, optic nerves showed a hypomyelination (0.844 ± 0.022) compared to control animals (0.832 ± 0.016) of large diameter myelinated fibers., Conclusions: We found that CC2D1B plays a role in developmental myelination in the central nervous system. These results suggest that CC2D1B could contribute to gene regulation during oligodendrocytes myelination in optic nerves., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Acheta, Hong, Jeanette, Brar, Yalamanchili, Feltri, Manzini, Belin and Poitelon.)
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- 2022
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34. Raising cGMP restores proteasome function and myelination in mice with a proteotoxic neuropathy.
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VerPlank JJS, Gawron J, Silvestri NJ, Feltri ML, Wrabetz L, and Goldberg AL
- Subjects
- Animals, HEK293 Cells, Humans, Mice, Myelin P0 Protein genetics, Myelin P0 Protein metabolism, Sciatic Nerve metabolism, Charcot-Marie-Tooth Disease metabolism, Proteasome Endopeptidase Complex metabolism
- Abstract
Agents that raise cyclic guanosine monophosphate (cGMP) by activating protein kinase G increase 26S proteasome activities, protein ubiquitination and degradation of misfolded proteins. Therefore, they may be useful in treating neurodegenerative and other diseases caused by an accumulation of misfolded proteins. Mutations in myelin protein zero (MPZ) cause the peripheral neuropathy Charcot-Marie-Tooth type 1B (CMT1B). In peripheral nerves of a mouse model of CMT1B, where the mutant MPZS63del is expressed, proteasome activities are reduced, mutant MPZS63del and polyubiquitinated proteins accumulate and the unfolded protein response (p-eif2α) is induced. In HEK293 cells, raising cGMP stimulated ubiquitination and degradation of MPZS63del, but not of wild-type MPZ. Treating S63del mice with the phosphodiesterase 5 inhibitor, sildenafil-to raise cGMP-increased proteasome activity in sciatic nerves and reduced the levels of polyubiquitinated proteins, the proteasome reporter ubG76V-GFP and p-elF2α. Furthermore, sildenafil treatment reduced the number of amyelinated axons, and increased myelin thickness and nerve conduction velocity in sciatic nerves. Thus, agents that raise cGMP, including those widely used in medicine, may be useful therapies for CMT1B and other proteotoxic diseases., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2022
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35. ACTL6a coordinates axonal caliber recognition and myelination in the peripheral nerve.
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Park HJ, Tsai E, Huang D, Weaver M, Frick L, Alcantara A, Moran JJ, Patzig J, Melendez-Vasquez CV, Crabtree GR, Feltri ML, Svaren J, and Casaccia P
- Abstract
Cells elaborate transcriptional programs in response to external signals. In the peripheral nerves, Schwann cells (SC) sort axons of given caliber and start the process of wrapping their membrane around them. We identify Actin-like protein 6a (ACTL6a), part of SWI/SNF chromatin remodeling complex, as critical for the integration of axonal caliber recognition with the transcriptional program of myelination. Nuclear levels of ACTL6A in SC are increased by contact with large caliber axons or nanofibers, and result in the eviction of repressive histone marks to facilitate myelination. Without Actl6a the SC are unable to coordinate caliber recognition and myelin production. Peripheral nerves in knockout mice display defective radial sorting, hypo-myelination of large caliber axons, and redundant myelin around small caliber axons, resulting in a clinical motor phenotype. Overall, this suggests that ACTL6A is a key component of the machinery integrating external signals for proper myelination of the peripheral nerve., Competing Interests: The authors declare no competing interests, (© 2022 The Authors.)
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- 2022
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36. Author Correction: Regulation of local GTP availability controls RAC1 activity and cell invasion.
- Author
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Bianchi-Smiraglia A, Wolff DW, Marston DJ, Deng Z, Han Z, Moparthy S, Wombacher RM, Mussell AL, Shen S, Chen J, Yun DH, O'Brien Cox A, Furdui CM, Hurley E, Feltri ML, Qu J, Hollis T, Kengne JBN, Fongang B, Sousa RJ, Kandel ME, Kandel ES, Hahn KM, and Nikiforov MA
- Published
- 2021
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37. Age-related neurodegeneration and cognitive impairments of NRMT1 knockout mice are preceded by misregulation of RB and abnormal neural stem cell development.
- Author
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Catlin JP, Marziali LN, Rein B, Yan Z, Feltri ML, and Schaner Tooley CE
- Subjects
- Animals, Animals, Newborn, Apoptosis, Behavior, Animal, Cell Cycle, Cerebral Ventricles pathology, Cognitive Dysfunction genetics, Cognitive Dysfunction pathology, Gene Expression Regulation, Glial Fibrillary Acidic Protein metabolism, Hippocampus pathology, Ki-67 Antigen metabolism, Maze Learning, Memory Disorders complications, Mice, Inbred C57BL, Mice, Knockout, Nerve Degeneration genetics, Nerve Degeneration pathology, Neural Stem Cells pathology, Neurons metabolism, Neurons pathology, RNA, Messenger genetics, RNA, Messenger metabolism, Retinoblastoma Protein metabolism, Spatial Memory, Stem Cell Niche, Mice, Aging pathology, Cognitive Dysfunction complications, Methyltransferases metabolism, Nerve Degeneration complications, Neural Stem Cells metabolism, Retinoblastoma Protein genetics
- Abstract
N-terminal methylation is an important posttranslational modification that regulates protein/DNA interactions and plays a role in many cellular processes, including DNA damage repair, mitosis, and transcriptional regulation. Our generation of a constitutive knockout mouse for the N-terminal methyltransferase NRMT1 demonstrated its loss results in severe developmental abnormalities and premature aging phenotypes. As premature aging is often accompanied by neurodegeneration, we more specifically examined how NRMT1 loss affects neural pathology and cognitive behaviors. Here we find that Nrmt1
-/- mice exhibit postnatal enlargement of the lateral ventricles, age-dependent striatal and hippocampal neurodegeneration, memory impairments, and hyperactivity. These morphological and behavior abnormalities are preceded by alterations in neural stem cell (NSC) development. Early expansion and differentiation of the quiescent NSC pool in Nrmt1-/- mice is followed by its subsequent depletion and many of the resulting neurons remain in the cell cycle and ultimately undergo apoptosis. These cell cycle phenotypes are reminiscent to those seen with loss of the NRMT1 target retinoblastoma protein (RB). Accordingly, we find misregulation of RB phosphorylation and degradation in Nrmt1-/- mice, and significant de-repression of RB target genes involved in cell cycle. We also identify novel de-repression of Noxa, an RB target gene that promotes apoptosis. These data identify Nα-methylation as a novel regulatory modification of RB transcriptional repression during neurogenesis and indicate that NRMT1 and RB work together to promote NSC quiescence and prevent neuronal apoptosis., (© 2021. The Author(s).)- Published
- 2021
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38. Regulation of local GTP availability controls RAC1 activity and cell invasion.
- Author
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Bianchi-Smiraglia A, Wolff DW, Marston DJ, Deng Z, Han Z, Moparthy S, Wombacher RM, Mussell AL, Shen S, Chen J, Yun DH, O'Brien Cox A, Furdui CM, Hurley E, Feltri ML, Qu J, Hollis T, Kengne JBN, Fongang B, Sousa RJ, Kandel ME, Kandel ES, Hahn KM, and Nikiforov MA
- Subjects
- Cell Membrane metabolism, Cell Movement, Guanosine Triphosphate chemistry, HEK293 Cells, Humans, IMP Dehydrogenase genetics, IMP Dehydrogenase metabolism, Kinetics, Protein Binding, rac1 GTP-Binding Protein chemistry, rac1 GTP-Binding Protein genetics, Guanosine Triphosphate metabolism, rac1 GTP-Binding Protein metabolism
- Abstract
Physiological changes in GTP levels in live cells have never been considered a regulatory step of RAC1 activation because intracellular GTP concentration (determined by chromatography or mass spectrometry) was shown to be substantially higher than the in vitro RAC1 GTP dissociation constant (RAC1-GTP Kd). Here, by combining genetically encoded GTP biosensors and a RAC1 activity biosensor, we demonstrated that GTP levels fluctuating around RAC1-GTP Kd correlated with changes in RAC1 activity in live cells. Furthermore, RAC1 co-localized in protrusions of invading cells with several guanylate metabolism enzymes, including rate-limiting inosine monophosphate dehydrogenase 2 (IMPDH2), which was partially due to direct RAC1-IMPDH2 interaction. Substitution of endogenous IMPDH2 with IMPDH2 mutants incapable of binding RAC1 did not affect total intracellular GTP levels but suppressed RAC1 activity. Targeting IMPDH2 away from the plasma membrane did not alter total intracellular GTP pools but decreased GTP levels in cell protrusions, RAC1 activity, and cell invasion. These data provide a mechanism of regulation of RAC1 activity by local GTP pools in live cells., (© 2021. The Author(s).)
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- 2021
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39. Mechanisms of demyelination and neurodegeneration in globoid cell leukodystrophy.
- Author
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Feltri ML, Weinstock NI, Favret J, Dhimal N, Wrabetz L, and Shin D
- Subjects
- Animals, Central Nervous System metabolism, Disease Models, Animal, Galactosylceramidase genetics, Galactosylceramidase metabolism, Genetic Therapy, Mice, Myelin Sheath metabolism, Leukodystrophy, Globoid Cell genetics, Leukodystrophy, Globoid Cell metabolism, Leukodystrophy, Globoid Cell therapy
- Abstract
Globoid cell leukodystrophy (GLD), also known as Krabbe disease, is a lysosomal storage disorder causing extensive demyelination in the central and peripheral nervous systems. GLD is caused by loss-of-function mutations in the lysosomal hydrolase, galactosylceramidase (GALC), which catabolizes the myelin sphingolipid galactosylceramide. The pathophysiology of GLD is complex and reflects the expression of GALC in a number of glial and neural cell types in both the central and peripheral nervous systems (CNS and PNS), as well as leukocytes and kidney in the periphery. Over the years, GLD has garnered a wide range of scientific and medical interests, especially as a model system to study gene therapy and novel preclinical therapeutic approaches to treat the spontaneous murine model for GLD. Here, we review recent findings in the field of Krabbe disease, with particular emphasis on novel aspects of GALC physiology, GLD pathophysiology, and therapeutic strategies., (© 2021 Wiley Periodicals LLC.)
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- 2021
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40. Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination.
- Author
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Della-Flora Nunes G, Wilson ER, Hurley E, He B, O'Malley BW, Poitelon Y, Wrabetz L, and Feltri ML
- Subjects
- Animals, Demyelinating Diseases pathology, Mice, Mice, Knockout, Myelin Sheath metabolism, Prohibitins, Schwann Cells enzymology, Up-Regulation, Demyelinating Diseases metabolism, Mechanistic Target of Rapamycin Complex 1 metabolism, Mitochondria metabolism, Proto-Oncogene Proteins c-jun metabolism, Repressor Proteins genetics, Schwann Cells metabolism
- Abstract
Schwann cell (SC) mitochondria are quickly emerging as an important regulator of myelin maintenance in the peripheral nervous system (PNS). However, the mechanisms underlying demyelination in the context of mitochondrial dysfunction in the PNS are incompletely understood. We recently showed that conditional ablation of the mitochondrial protein Prohibitin 1 (PHB1) in SCs causes a severe and fast progressing demyelinating peripheral neuropathy in mice, but the mechanism that causes failure of myelin maintenance remained unknown. Here, we report that mTORC1 and c-Jun are continuously activated in the absence of Phb1 , likely as part of the SC response to mitochondrial damage. Moreover, we demonstrate that these pathways are involved in the demyelination process, and that inhibition of mTORC1 using rapamycin partially rescues the demyelinating pathology. Therefore, we propose that mTORC1 and c-Jun may play a critical role as executioners of demyelination in the context of perturbations to SC mitochondria., Competing Interests: GD, EW, EH, BH, BO, YP, LW, MF No competing interests declared, (© 2021, Della-Flora Nunes et al.)
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- 2021
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41. Schwann cell interactions during the development of the peripheral nervous system.
- Author
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Wilson ER, Della-Flora Nunes G, Weaver MR, Frick LR, and Feltri ML
- Subjects
- Axons metabolism, Cell Communication, Neuroglia metabolism, Peripheral Nervous System, Schwann Cells physiology
- Abstract
Schwann cells play a critical role in the development of the peripheral nervous system (PNS), establishing important relationships both with the extracellular milieu and other cell types, particularly neurons. In this review, we discuss various Schwann cell interactions integral to the proper establishment, spatial arrangement, and function of the PNS. We include signals that cascade onto Schwann cells from axons and from the extracellular matrix, bidirectional signals that help to establish the axo-glial relationship and how Schwann cells in turn support the axon. Further, we speculate on how Schwann cell interactions with other components of the developing PNS ultimately promote the complete construction of the peripheral nerve., (© 2020 Wiley Periodicals, Inc.)
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- 2021
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42. Prohibitin 1 is essential to preserve mitochondria and myelin integrity in Schwann cells.
- Author
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Della-Flora Nunes G, Wilson ER, Marziali LN, Hurley E, Silvestri N, He B, O'Malley BW, Beirowski B, Poitelon Y, Wrabetz L, and Feltri ML
- Subjects
- Animals, Aspartate-Ammonia Ligase genetics, Aspartate-Ammonia Ligase metabolism, Axons metabolism, Axons ultrastructure, Endoplasmic Reticulum Chaperone BiP, Eukaryotic Initiation Factor-2 genetics, Eukaryotic Initiation Factor-2 metabolism, Female, Femoral Nerve pathology, Heat-Shock Proteins genetics, Heat-Shock Proteins metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria pathology, Myelin Sheath metabolism, Myelin Sheath pathology, Phosphoenolpyruvate Carboxykinase (ATP) genetics, Phosphoenolpyruvate Carboxykinase (ATP) metabolism, Prohibitins, Protein Isoforms genetics, Protein Isoforms metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Repressor Proteins deficiency, Schwann Cells pathology, Sciatic Nerve pathology, Stress, Physiological, Tibial Nerve pathology, Transcription Factor CHOP genetics, Transcription Factor CHOP metabolism, X-Box Binding Protein 1 genetics, X-Box Binding Protein 1 metabolism, gamma-Glutamylcyclotransferase genetics, gamma-Glutamylcyclotransferase metabolism, Femoral Nerve metabolism, Mitochondria metabolism, Repressor Proteins genetics, Schwann Cells metabolism, Sciatic Nerve metabolism, Tibial Nerve metabolism
- Abstract
In peripheral nerves, Schwann cells form myelin and provide trophic support to axons. We previously showed that the mitochondrial protein prohibitin 2 can localize to the axon-Schwann-cell interface and is required for developmental myelination. Whether the homologous protein prohibitin 1 has a similar role, and whether prohibitins also play important roles in Schwann cell mitochondria is unknown. Here, we show that deletion of prohibitin 1 in Schwann cells minimally perturbs development, but later triggers a severe demyelinating peripheral neuropathy. Moreover, mitochondria are heavily affected by ablation of prohibitin 1 and demyelination occurs preferentially in cells with apparent mitochondrial loss. Furthermore, in response to mitochondrial damage, Schwann cells trigger the integrated stress response, but, contrary to what was previously suggested, this response is not detrimental in this context. These results identify a role for prohibitin 1 in myelin integrity and advance our understanding about the Schwann cell response to mitochondrial damage.
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- 2021
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43. Calcineurin Activity Is Increased in Charcot-Marie-Tooth 1B Demyelinating Neuropathy.
- Author
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Sidoli M, Reed CB, Scapin C, Paez P, Cavener DR, Kaufman RJ, D'Antonio M, Feltri ML, and Wrabetz L
- Subjects
- Animals, Charcot-Marie-Tooth Disease genetics, Demyelinating Diseases genetics, Demyelinating Diseases metabolism, Female, Male, Mice, Mice, Transgenic, Mutation, Myelin P0 Protein genetics, Calcineurin metabolism, Charcot-Marie-Tooth Disease metabolism, Endoplasmic Reticulum Stress physiology, Schwann Cells metabolism, eIF-2 Kinase metabolism
- Abstract
Schwann cells produce a considerable amount of lipids and proteins to form myelin in the PNS. For this reason, the quality control of myelin proteins is crucial to ensure proper myelin synthesis. Deletion of serine 63 from P0 (P0S63del) protein in myelin forming Schwann cells causes Charcot-Marie-Tooth type 1B neuropathy in humans and mice. Misfolded P0S63del accumulates in the ER of Schwann cells where it elicits the unfolded protein response (UPR). PERK is the UPR transducer that attenuates global translation and reduces ER stress by phosphorylating the translation initiation factor eIF2alpha. Paradoxically, Perk ablation in P0S63del Schwann cells (S63del/ Perk
SCKO ) reduced the level of P-eIF2alpha, leaving UPR markers upregulated, yet unexpectedly improved S63del myelin defects in vivo We therefore investigated the hypothesis that PERK may interfere with signals outside of the UPR and specifically with calcineurin/NFATc4 pro-myelinating pathway. Using mouse genetics including females and males in our experimental setting, we show that PERK and calcineurin interact in P0S63del nerves and that calcineurin activity and NFATc4 nuclear localization are increased in S63del Schwann cells, without altering EGR2/KROX20 expression. Moreover, genetic manipulation of the calcineurin subunits appears to be either protective or toxic in S63del in a context-dependent manner, suggesting that Schwann cells are highly sensitive to alterations of calcineurin activity. SIGNIFICANCE STATEMENT Our work shows a novel activity and function for calcineurin in Schwann cells in the context of ER stress. Schwann cells expressing the S63del mutation in P0 protein induce the unfolded protein response and upregulate calcineurin activity. Calcineurin interacts with the ER stress transducer PERK, but the relationship between the UPR and calcineurin in Schwann cells is unclear. Here we propose a protective role for calcineurin in S63del neuropathy, although Schwann cells appear to be very sensitive to its regulation. The paper uncovers a new important role for calcineurin in a demyelinating diseases., (Copyright © 2021 the authors.)- Published
- 2021
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44. Rac1 and Rac3 have opposite functions in Schwann cells during developmental myelination.
- Author
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Pellegatta M, Berti C, Hurley E, Palmisano M, de Curtis I, Feltri ML, and Frick LR
- Subjects
- Animals, Axons metabolism, Cell Differentiation, Mice, Mice, Knockout, Neuropeptides genetics, Phosphorylation, p21-Activated Kinases metabolism, rac1 GTP-Binding Protein genetics, Myelin Sheath metabolism, Neuropeptides metabolism, Schwann Cells physiology, rac GTP-Binding Proteins metabolism, rac1 GTP-Binding Protein metabolism
- Abstract
Small Rho GTPases such as Cdc42 and Rac1 regulate peripheral myelination during development. Deletion of Rac1 in Schwann cell conditional knockout mice causes a delay in the process of radial sorting, followed by hypomyelination as well as defective PAK1 activation and high number of immature Oct6
+ Schwann cells. Rac3 has been shown to have redundant, specific and even opposite functions to Rac1 depending on the cell type, age and other factors. In neuronal cells, evidence suggests that Rac3 may oppose Rac1 by disrupting PAK1-GIT1-Paxillin signaling thus preventing cell differentiation and extension of lamellipodia. Therefore, we tested if these Rho GTPases have similar or opposite functions in Schwann cells, by deleting the genes for both proteins in mice during peripheral myelination. At P30, global deletion of Rac3 alleviates the developmental defects on axonal sorting and hypomyelination that are caused by Schwann cell conditional ablation of Rac1. Moreover, Rac3 deletion also reverses the arrest of Schwann cells at the Oct6+ stage and ameliorates the defects in PAK1 phosphorylation observed in Rac1 deficient mice. This partial rescue of the phenotype declines later on with aging. Since double transgenic animals showed dysmyelination without axonal degeneration at P60, we postulate that this deterioration is not likely due to loss of Rac3 in neurons, but it seems to be a Schwann cell-specific defect in the maintenance of myelin., (Copyright © 2021. Published by Elsevier B.V.)- Published
- 2021
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45. YAP and TAZ regulate Schwann cell proliferation and differentiation during peripheral nerve regeneration.
- Author
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Jeanette H, Marziali LN, Bhatia U, Hellman A, Herron J, Kopec AM, Feltri ML, Poitelon Y, and Belin S
- Subjects
- Animals, Cell Cycle Proteins, Cell Differentiation, Cell Proliferation, Mice, Nerve Regeneration, Schwann Cells metabolism, Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Hippo Signaling Pathway
- Abstract
YAP and TAZ are effectors of the Hippo pathway that controls multicellular development by integrating chemical and mechanical signals. Peripheral nervous system development depends on the Hippo pathway. We previously showed that loss of YAP and TAZ impairs the development of peripheral nerve as well as Schwann cell myelination. The role of the Hippo pathway in peripheral nerve regeneration has just started to be explored. After injury, Schwann cells adopt new identities to promote regeneration by converting to a repair-promoting phenotype. While the reprogramming of Schwann cells to repair cells has been well characterized, the maintenance of such repair phenotype cannot be sustained for a very long period, which limits nerve repair in human. First, we show that short or long-term myelin maintenance is not affected by defect in YAP and TAZ expression. Using crush nerve injury and conditional mutagenesis in mice, we also show that YAP and TAZ are regulators of repair Schwann cell proliferation and differentiation. We found that YAP and TAZ are required in repair Schwann cells for their redifferentiation into myelinating Schwann cell following crush injury. In this present study, we describe how the Hippo pathway and YAP and TAZ regulate remyelination over time during peripheral nerve regeneration., (© 2020 The Authors. Glia published by Wiley Periodicals LLC.)
- Published
- 2021
- Full Text
- View/download PDF
46. Heparanome-Mediated Rescue of Oligodendrocyte Progenitor Quiescence following Inflammatory Demyelination.
- Author
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Saraswat D, Welliver RR, Ravichandar R, Tripathi A, Polanco JJ, Broome J, Hurley E, Dutta R, Feltri ML, and Sim FJ
- Subjects
- Animals, Cell Differentiation physiology, Cell Proliferation physiology, Demyelinating Autoimmune Diseases, CNS pathology, Demyelinating Diseases metabolism, Demyelinating Diseases pathology, Humans, Inflammation metabolism, Inflammation pathology, Mice, Mice, Knockout, Demyelinating Autoimmune Diseases, CNS metabolism, Heparan Sulfate Proteoglycans metabolism, Interferon-gamma metabolism, Oligodendrocyte Precursor Cells metabolism
- Abstract
The proinflammatory cytokine IFN-γ, which is chronically elevated in multiple sclerosis, induces pathologic quiescence in human oligodendrocyte progenitor cells (OPCs) via upregulation of the transcription factor PRRX1. In this study using animals of both sexes, we investigated the role of heparan sulfate proteoglycans in the modulation of IFN-γ signaling following demyelination. We found that IFN-γ profoundly impaired OPC proliferation and recruitment following adult spinal cord demyelination. IFN-γ-induced quiescence was mediated by direct signaling in OPCs as conditional genetic ablation of IFN γ R1 ( Ifngr1 ) in adult NG2
+ OPCs completely abrogated these inhibitory effects. Intriguingly, OPC-specific IFN-γ signaling contributed to failed oligodendrocyte differentiation, which was associated with hyperactive Wnt/Bmp target gene expression in OPCs. We found that PI-88, a heparan sulfate mimetic, directly antagonized IFN-γ to rescue human OPC proliferation and differentiation in vitro and blocked the IFN-γ-mediated inhibitory effects on OPC recruitment in vivo Importantly, heparanase modulation by PI-88 or OGT2155 in demyelinated lesions rescued IFN-γ-mediated axonal damage and demyelination. In addition to OPC-specific effects, IFN-γ-augmented lesions were characterized by increased size, reactive astrogliosis, and proinflammatory microglial/macrophage activation along with exacerbated axonal injury and cell death. Heparanase inhibitor treatment rescued many of the negative IFN-γ-induced sequelae suggesting a profound modulation of the lesion environment. Together, these results suggest that the modulation of the heparanome represents a rational approach to mitigate the negative effects of proinflammatory signaling and rescuing pathologic quiescence in the inflamed and demyelinated human brain. SIGNIFICANCE STATEMENT The failure of remyelination in multiple sclerosis contributes to neurologic dysfunction and neurodegeneration. The activation and proliferation of oligodendrocyte progenitor cells (OPCs) is a necessary step in the recruitment phase of remyelination. Here, we show that the proinflammatory cytokine interferon-γ directly acts on OPCs to induce pathologic quiescence and thereby limit recruitment following demyelination. Heparan sulfate is a highly structured sulfated carbohydrate polymer that is present on the cell surface and regulates several aspects of the signaling microenvironment. We find that pathologic interferon-γ can be blocked by modulation of the heparanome following demyelination using either a heparan mimetic or by treatment with heparanase inhibitor. These studies establish the potential for modulation of heparanome as a regenerative approach in demyelinating disease., (Copyright © 2021 the authors.)- Published
- 2021
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47. The Hippo pathway: Horizons for innovative treatments of peripheral nerve diseases.
- Author
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Feltri ML, Weaver MR, Belin S, and Poitelon Y
- Subjects
- Animals, Humans, Adaptor Proteins, Signal Transducing metabolism, Gene Expression Regulation, Enzymologic physiology, Intracellular Signaling Peptides and Proteins metabolism, Peripheral Nervous System Diseases enzymology, Peripheral Nervous System Diseases genetics, Peripheral Nervous System Diseases therapy, Protein Serine-Threonine Kinases metabolism, Signal Transduction physiology
- Abstract
Initially identified in Drosophila, the Hippo signaling pathway regulates how cells respond to their environment by controlling proliferation, migration and differentiation. Many recent studies have focused on characterizing Hippo pathway function and regulation in mammalian cells. Here, we present a brief overview of the major components of the Hippo pathway, as well as their regulation and function. We comprehensively review the studies that have contributed to our understanding of the Hippo pathway in the function of the peripheral nervous system and in peripheral nerve diseases. Finally, we discuss innovative approaches that aim to modulate Hippo pathway components in diseases of the peripheral nervous system., (© 2021 Peripheral Nerve Society.)
- Published
- 2021
- Full Text
- View/download PDF
48. α V integrins in Schwann cells promote attachment to axons, but are dispensable in vivo.
- Author
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Catignas KK, Frick LR, Pellegatta M, Hurley E, Kolb Z, Addabbo K, McCarty JH, Hynes RO, van der Flier A, Poitelon Y, Wrabetz L, and Feltri ML
- Subjects
- Animals, Axons, Integrin alphaV, Integrins, Mice, Oligopeptides, Schwann Cells
- Abstract
In the developing peripheral nervous system, Schwann cells (SCs) extend their processes to contact, sort, and myelinate axons. The mechanisms that contribute to the interaction between SCs and axons are just beginning to be elucidated. Using a SC-neuron coculture system, we demonstrate that Arg-Gly-Asp (RGD) peptides that inhibit α
V -containing integrins delay the extension of SCs elongating on axons. αV integrins in SC localize to sites of contact with axons and are expressed early in development during radial sorting and myelination. Short interfering RNA-mediated knockdown of the αV integrin subunit also delays SC extension along axons in vitro, suggesting that αV -containing integrins participate in axo-glial interactions. However, mice lacking the αV subunit in SCs, alone or in combination with the potentially compensating α5 subunit, or the αV partners β3 or β8 , myelinate normally during development and remyelinate normally after nerve crush, indicating that overlapping or compensatory mechanisms may hide the in vivo role of RGD-binding integrins., (© 2020 Wiley Periodicals LLC.)- Published
- 2021
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49. Brainstem development requires galactosylceramidase and is critical for pathogenesis in a model of Krabbe disease.
- Author
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Weinstock NI, Kreher C, Favret J, Nguyen D, Bongarzone ER, Wrabetz L, Feltri ML, and Shin D
- Subjects
- Animals, Brain Stem embryology, Disease Models, Animal, Gene Expression Regulation, Developmental, Hematopoietic Stem Cell Transplantation, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurons metabolism, Phenotype, Psychosine metabolism, Tamoxifen, Transcriptome, Brain Stem enzymology, Brain Stem growth & development, Brain Stem metabolism, Galactosylceramidase genetics, Galactosylceramidase metabolism, Leukodystrophy, Globoid Cell genetics, Leukodystrophy, Globoid Cell metabolism
- Abstract
Krabbe disease (KD) is caused by a deficiency of galactosylceramidase (GALC), which induces demyelination and neurodegeneration due to accumulation of cytotoxic psychosine. Hematopoietic stem cell transplantation (HSCT) improves clinical outcomes in KD patients only if delivered pre-symptomatically. Here, we hypothesize that the restricted temporal efficacy of HSCT reflects a requirement for GALC in early brain development. Using a novel Galc floxed allele, we induce ubiquitous GALC ablation (Galc-iKO) at various postnatal timepoints and identify a critical period of vulnerability to GALC ablation between P4-6 in mice. Early Galc-iKO induction causes a worse KD phenotype, higher psychosine levels in the rodent brainstem and spinal cord, and a significantly shorter life-span of the mice. Intriguingly, GALC expression peaks during this critical developmental period in mice. Further analysis of this mouse model reveals a cell autonomous role for GALC in the development and maturation of immature T-box-brain-1 positive brainstem neurons. These data identify a perinatal developmental period, in which neuronal GALC expression influences brainstem development that is critical for KD pathogenesis.
- Published
- 2020
- Full Text
- View/download PDF
50. Phosphorylation of eIF2α Promotes Schwann Cell Differentiation and Myelination in CMT1B Mice with Activated UPR.
- Author
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Scapin C, Ferri C, Pettinato E, Bianchi F, Del Carro U, Feltri ML, Kaufman RJ, Wrabetz L, and D'Antonio M
- Subjects
- Animals, Charcot-Marie-Tooth Disease genetics, Demyelinating Diseases genetics, Demyelinating Diseases pathology, Female, MAP Kinase Signaling System genetics, Male, Mice, Mice, Transgenic, Phosphorylation, Protein Phosphatase 1 metabolism, Unfolded Protein Response genetics, Cell Differentiation genetics, Charcot-Marie-Tooth Disease physiopathology, Eukaryotic Initiation Factor-2 genetics, Myelin Sheath genetics, Schwann Cells
- Abstract
Myelin Protein Zero (MPZ/P0) is the most abundant glycoprotein of peripheral nerve myelin. P0 is synthesized by myelinating Schwann cells, processed in the endoplasmic reticulum (ER) and delivered to myelin via the secretory pathway. The mutant P0S63del (deletion of serine 63 in the extracellular domain of P0), that causes Charcot-Marie-Tooth type 1B (CMT1B) neuropathy in humans and a similar demyelinating neuropathy in transgenic mice, is instead retained the ER where it activates an unfolded protein response. Under ER-stress conditions, protein kinase R-like endoplasmic reticulum kinase (PERK) phosphorylates eukaryotic initiation factor 2α (eIF2α) to attenuate global translation, thus reducing the misfolded protein overload in the ER. Genetic and pharmacological inactivation of Gadd34 (damage-inducible protein 34), a subunit of the PP1 phosphatase complex that promotes the dephosphorylation of eIF2α, prolonged eIF2α phosphorylation and improved motor, neurophysiological, and morphologic deficits in S63del mice. However, PERK ablation in S63del Schwann cells ameliorated, rather than worsened, S63del neuropathy despite reduced levels of phosphorylated eIF2α. These contradictory findings prompted us to genetically explore the role of eIF2α phosphorylation in P0S63del-CMT1B neuropathy through the generation of mice in which eIF2α cannot be phosphorylated specifically in Schwann cells. Morphologic and electrophysiological analysis of male and female S63del mice showed a worsening of the neuropathy in the absence of eIF2α phosphorylation. However, we did not detect significant changes in ER stress levels, but rather a dramatic increase of the MEK/ERK/c-Jun pathway accompanied by a reduction in expression of myelin genes and a delay in Schwann cell differentiation. Our results support the hypothesis that eIF2α phosphorylation is protective in CMT1B and unveil a possible cross talk between eIF2α and the MEK/ERK pathway in neuropathic nerves. SIGNIFICANCE STATEMENT In the P0S63del (deletion of serine 63 in the extracellular domain of P0) mouse model of Charcot-Marie-Tooth type 1B (CMT1B), the genetic and pharmacological inhibition of Gadd34 (damage-inducible protein 34) prolonged eukaryotic initiation factor 2α (eIF2α) phosphorylation, leading to a proteostatic rebalance that significantly ameliorated the neuropathy. Yet, ablation of protein kinase R-like endoplasmic reticulum kinase (PERK) also ameliorated the S63del neuropathy, despite reduced levels of eIF2α phosphorylation (P-eIF2α). In this study, we provide genetic evidence that eIF2α phosphorylation has a protective role in CMT1B Schwann cells by limiting ERK/c-Jun hyperactivation. Our data support the targeting of the P-eIF2α/Gadd34 complex as a therapeutic avenue in CMT1B and also suggest that PERK may hamper myelination via mechanisms outside its role in the unfolded protein response., (Copyright © 2020 the authors.)
- Published
- 2020
- Full Text
- View/download PDF
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