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1.
Ann Neurol ; 87(3): 339-346, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31943325

RESUMEN

OBJECTIVE: SCN8A encephalopathy is a developmental and epileptic encephalopathy (DEE) caused by de novo gain-of-function mutations of sodium channel Nav 1.6 that result in neuronal hyperactivity. Affected individuals exhibit early onset drug-resistant seizures, developmental delay, and cognitive impairment. This study was carried out to determine whether reducing the abundance of the Scn8a transcript with an antisense oligonucleotide (ASO) would delay seizure onset and prolong survival in a mouse model of SCN8A encephalopathy. METHODS: ASO treatment was tested in a conditional mouse model with Cre-dependent expression of the pathogenic patient SCN8A mutation p.Arg1872Trp (R1872W). This model exhibits early onset of seizures, rapid progression, and 100% penetrance. An Scn1a +/- haploinsufficient mouse model of Dravet syndrome was also treated. ASO was administered by intracerebroventricular injection at postnatal day 2, followed in some cases by stereotactic injection at postnatal day 30. RESULTS: We observed a dose-dependent increase in length of survival from 15 to 65 days in the Scn8a-R1872W/+ mice treated with ASO. Electroencephalographic recordings were normal prior to seizure onset. Weight gain and activity in an open field were unaffected, but treated mice were less active in a wheel running assay. A single treatment with Scn8a ASO extended survival of Dravet syndrome mice from 3 weeks to >5 months. INTERPRETATION: Reduction of Scn8a transcript by 25 to 50% delayed seizure onset and lethality in mouse models of SCN8A encephalopathy and Dravet syndrome. Reduction of SCN8A transcript is a promising approach to treatment of intractable childhood epilepsies. Ann Neurol 2020;87:339-346.


Asunto(s)
Encefalopatías/prevención & control , Epilepsias Mioclónicas/prevención & control , Canal de Sodio Activado por Voltaje NAV1.6/efectos de los fármacos , Animales , Encefalopatías/complicaciones , Encefalopatías/mortalidad , Relación Dosis-Respuesta a Droga , Epilepsias Mioclónicas/complicaciones , Epilepsias Mioclónicas/mortalidad , Femenino , Infusiones Intraventriculares , Masculino , Ratones , Ratones Transgénicos , Mutación , Canal de Sodio Activado por Voltaje NAV1.6/administración & dosificación , Oligonucleótidos Antisentido/farmacología , Convulsiones/complicaciones , Convulsiones/prevención & control
2.
Hum Mol Genet ; 27(14): 2443-2453, 2018 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-29688489

RESUMEN

The signaling lipid phosphatidylinositol 3,5-bisphosphate, PI(3,5)P2, functions in vesicular trafficking through the endo-lysosomal compartment. Cellular levels of PI(3,5)P2 are regulated by an enzyme complex comprised of the kinase PIKFYVE, the phosphatase FIG4, and the scaffold protein VAC14. Mutations of human FIG4 cause inherited disorders including Charcot-Marie-Tooth disease type 4J, polymicrogyria with epilepsy, and Yunis-Varón syndrome. Constitutive Fig4-/- mice exhibit intention tremor, spongiform degeneration of neural tissue, hypomyelination, and juvenile lethality. To determine whether PI(3,5)P2 is required in the adult, we generated Fig4flox/-; CAG-creER mice and carried out tamoxifen-induced gene ablation. Global ablation in adulthood leads to wasting, tremor, and motor impairment. Death follows within 2 months of tamoxifen treatment, demonstrating a life-long requirement for Fig4. Histological examinations of the sciatic nerve revealed profound Wallerian degeneration of myelinated fibers, but not C-fiber axons in Remak bundles. In optic nerve sections, myelinated fibers appear morphologically intact and carry compound action potentials at normal velocity and amplitude. However, when iKO mice are challenged with a chemical white matter lesion, repair of damaged CNS myelin is significantly delayed, demonstrating a novel role for Fig4 in remyelination. Thus, in the adult PNS Fig4 is required to protect myelinated axons from Wallerian degeneration. In the adult CNS, Fig4 is dispensable for fiber stability and nerve conduction, but is required for the timely repair of damaged white matter. The greater vulnerability of the PNS to Fig4 deficiency in the mouse is consistent with clinical observations in patients with Charcot-Marie-Tooth disease.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Flavoproteínas/genética , Sistema Nervioso/metabolismo , Fosfoinosítido Fosfatasas/genética , Monoéster Fosfórico Hidrolasas/genética , Animales , Axones/patología , Sistema Nervioso Central/fisiopatología , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Displasia Cleidocraneal/genética , Displasia Cleidocraneal/fisiopatología , Displasia Ectodérmica/genética , Displasia Ectodérmica/fisiopatología , Humanos , Deformidades Congénitas de las Extremidades/genética , Deformidades Congénitas de las Extremidades/fisiopatología , Ratones , Ratones Transgénicos , Micrognatismo/genética , Micrognatismo/fisiopatología , Mutación , Sistema Nervioso/patología , Neuronas/patología , Sistema Nervioso Periférico/fisiopatología , Fosfatidilinositol 3-Quinasas/genética , Fosfatos de Fosfatidilinositol/genética , Fosfatos de Fosfatidilinositol/metabolismo , Polimicrogiria/genética , Polimicrogiria/fisiopatología , Nervio Ciático/fisiopatología
3.
Cell Rep ; 43(3): 113931, 2024 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-38492223

RESUMEN

In adult mammals, injured retinal ganglion cells (RGCs) fail to spontaneously regrow severed axons, resulting in permanent visual deficits. Robust axon growth, however, is observed after intra-ocular injection of particulate ß-glucan isolated from yeast. Blood-borne myeloid cells rapidly respond to ß-glucan, releasing numerous pro-regenerative factors. Unfortunately, the pro-regenerative effects are undermined by retinal damage inflicted by an overactive immune system. Here, we demonstrate that protection of the inflamed vasculature promotes immune-mediated RGC regeneration. In the absence of microglia, leakiness of the blood-retina barrier increases, pro-inflammatory neutrophils are elevated, and RGC regeneration is reduced. Functional ablation of the complement receptor 3 (CD11b/integrin-αM), but not the complement components C1q-/- or C3-/-, reduces ocular inflammation, protects the blood-retina barrier, and enhances RGC regeneration. Selective targeting of neutrophils with anti-Ly6G does not increase axogenic neutrophils but protects the blood-retina barrier and enhances RGC regeneration. Together, these findings reveal that protection of the inflamed vasculature promotes neuronal regeneration.


Asunto(s)
Traumatismos del Nervio Óptico , beta-Glucanos , Animales , Neutrófilos , Regeneración Nerviosa/fisiología , Células Ganglionares de la Retina/fisiología , Axones/fisiología , Mamíferos
4.
Elife ; 112022 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-36515985

RESUMEN

Upon trauma, the adult murine peripheral nervous system (PNS) displays a remarkable degree of spontaneous anatomical and functional regeneration. To explore extrinsic mechanisms of neural repair, we carried out single-cell analysis of naïve mouse sciatic nerve, peripheral blood mononuclear cells, and crushed sciatic nerves at 1 day, 3 days, and 7 days following injury. During the first week, monocytes and macrophages (Mo/Mac) rapidly accumulate in the injured nerve and undergo extensive metabolic reprogramming. Proinflammatory Mo/Mac with a high glycolytic flux dominate the early injury response and rapidly give way to inflammation resolving Mac, programmed toward oxidative phosphorylation. Nerve crush injury causes partial leakiness of the blood-nerve barrier, proliferation of endoneurial and perineurial stromal cells, and entry of opsonizing serum proteins. Micro-dissection of the nerve injury site and distal nerve, followed by single-cell RNA-sequencing, identified distinct immune compartments, triggered by mechanical nerve wounding and Wallerian degeneration, respectively. This finding was independently confirmed with Sarm1-/- mice, in which Wallerian degeneration is greatly delayed. Experiments with chimeric mice showed that wildtype immune cells readily enter the injury site in Sarm1-/- mice, but are sparse in the distal nerve, except for Mo. We used CellChat to explore intercellular communications in the naïve and injured PNS and report on hundreds of ligand-receptor interactions. Our longitudinal analysis represents a new resource for neural tissue regeneration, reveals location- specific immune microenvironments, and reports on large intercellular communication networks. To facilitate mining of scRNAseq datasets, we generated the injured sciatic nerve atlas (iSNAT): https://cdb-rshiny.med.umich.edu/Giger_iSNAT/.


Asunto(s)
Traumatismos de los Nervios Periféricos , Degeneración Walleriana , Ratones , Animales , Degeneración Walleriana/metabolismo , Degeneración Walleriana/patología , Leucocitos Mononucleares , Nervio Ciático/metabolismo , Degeneración Nerviosa , Compresión Nerviosa , Traumatismos de los Nervios Periféricos/metabolismo , Regeneración Nerviosa , Proteínas del Citoesqueleto/metabolismo , Proteínas del Dominio Armadillo/metabolismo
5.
Elife ; 92020 12 02.
Artículo en Inglés | MEDLINE | ID: mdl-33263277

RESUMEN

Sciatic nerve crush injury triggers sterile inflammation within the distal nerve and axotomized dorsal root ganglia (DRGs). Granulocytes and pro-inflammatory Ly6Chigh monocytes infiltrate the nerve first and rapidly give way to Ly6Cnegative inflammation-resolving macrophages. In axotomized DRGs, few hematogenous leukocytes are detected and resident macrophages acquire a ramified morphology. Single-cell RNA-sequencing of injured sciatic nerve identifies five macrophage subpopulations, repair Schwann cells, and mesenchymal precursor cells. Macrophages at the nerve crush site are molecularly distinct from macrophages associated with Wallerian degeneration. In the injured nerve, macrophages 'eat' apoptotic leukocytes, a process called efferocytosis, and thereby promote an anti-inflammatory milieu. Myeloid cells in the injured nerve, but not axotomized DRGs, strongly express receptors for the cytokine GM-CSF. In GM-CSF-deficient (Csf2-/-) mice, inflammation resolution is delayed and conditioning-lesion-induced regeneration of DRG neuron central axons is abolished. Thus, carefully orchestrated inflammation resolution in the nerve is required for conditioning-lesion-induced neurorepair.


Asunto(s)
Ganglios Espinales/inmunología , Leucocitos/inmunología , Macrófagos/inmunología , Regeneración Nerviosa , Traumatismos de los Nervios Periféricos/inmunología , Fagocitosis , Nervio Ciático/inmunología , Animales , Apoptosis , Células Cultivadas , Subunidad beta Común de los Receptores de Citocinas/genética , Subunidad beta Común de los Receptores de Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Mediadores de Inflamación/metabolismo , Leucocitos/metabolismo , Leucocitos/patología , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/inmunología , Monocitos/metabolismo , Proyección Neuronal , Traumatismos de los Nervios Periféricos/genética , Traumatismos de los Nervios Periféricos/metabolismo , Traumatismos de los Nervios Periféricos/patología , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Nervio Ciático/lesiones , Nervio Ciático/metabolismo , Nervio Ciático/patología , Transducción de Señal
6.
Stem Cells Transl Med ; 3(5): 620-31, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24657963

RESUMEN

Induced pluripotent stem cells (iPSCs) show considerable promise for cell replacement therapies for Huntington's disease (HD). Our laboratory has demonstrated that tail-tip fibroblasts, reprogrammed into iPSCs via two adenoviruses, can survive and differentiate into neuronal lineages following transplantation into healthy adult rats. However, the ability of these cells to survive, differentiate, and restore function in a damaged brain is unknown. To this end, adult rats received a regimen of 3-nitropropionic acid (3-NP) to induce behavioral and neuropathological deficits that resemble HD. At 7, 21, and 42 days after the initiation of 3-NP or vehicle, the rats received intrastriatal bilateral transplantation of iPSCs. All rats that received 3-NP and vehicle treatment displayed significant motor impairment, whereas those that received iPSC transplantation after 3-NP treatment had preserved motor function. Histological analysis of the brains of these rats revealed significant decreases in optical densitometric measures in the striatum, lateral ventricle enlargement, as well as an increase in striosome size in all rats receiving 3-NP when compared with sham rats. The 3-NP-treated rats given transplants of iPSCs in the 7- or 21-day groups did not exhibit these deficits. Transplantation of iPSCs at the late-stage (42-day) time point did not protect against the 3-NP-induced neuropathology, despite preserving motor function. Transplanted iPSCs were found to survive and differentiate into region-specific neurons in the striatum of 3-NP rats, at all transplantation time points. Taken together, these results suggest that transplantation of adenovirus-generated iPSCs may provide a potential avenue for therapeutic treatment of HD.


Asunto(s)
Adenoviridae , Cuerpo Estriado , Enfermedad de Huntington , Células Madre Pluripotentes Inducidas , Trasplante de Células Madre , Transducción Genética , Animales , Conducta Animal , Convulsivantes/efectos adversos , Convulsivantes/farmacología , Modelos Animales de Enfermedad , Femenino , Enfermedad de Huntington/inducido químicamente , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/patología , Enfermedad de Huntington/terapia , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/trasplante , Masculino , Nitrocompuestos/efectos adversos , Nitrocompuestos/farmacología , Propionatos/efectos adversos , Propionatos/farmacología , Ratas , Ratas Sprague-Dawley
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