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Diffusion, spread, and migration of botulinum toxin.

Botulinum toxin (BoNT) is an acetylcholine release inhibitor and a neuromuscular blocking agent used for the treatment of a variety of neurologic and medical conditions. The efficacy and safety of BoNT depends on accurate selection and identification of intended targets but also may be determined by other factors, including physical spread of the molecule from the injection site, passive diffusion, and migration to distal sites via axonal or hematogenous transport. The passive kinetic dispersion of the toxin away from the injection site in a gradient-dependent manner may also play a role in to

Corrective GUSB transfer to the canine mucopolysaccharidosis VII brain.

Severe deficiency in lysosomal β-glucuronidase (β-glu) enzymatic activity results in mucopolysaccharidosis (MPS) VII, an orphan disease with symptoms often appearing in early childhood. Symptoms are variable, but many patients have multiple organ disorders including neurological defects. At the cellular level, deficiency in β-glu activity leads to abnormal accumulation of glycosaminoglycans (GAGs), and secondary accumulation of GM2 and GM3 gangliosides, which have been linked to neuroinflammation. There have been encouraging gene transfer studies in the MPS VII mouse brain, but this is the fir

Merits of combination cortical, subcortical, and cerebellar injections for the treatment of Niemann-Pick disease type A.

Niemann-Pick disease Type A (NPA) is a neuronopathic lysosomal storage disease (LSD) caused by the loss of acid sphingomyelinase (ASM). The … resulted in efficacious levels of enzyme in broad regions of the brain that was aided, in part, by axonal transport of adeno-associated virus (AAV) and movement through the perivascular space. This study demonstrates that a combination cortical, subcortical, and cerebellar injection protocol could provide therapeutic levels of hASM to regions of the NHP brain tha …

Temporal and cell-specific deletion establishes that neuronal Npc1 deficiency is sufficient to mediate neurodegeneration.

Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal storage disorder caused by mutations in the NPC1 or NPC2 genes. Loss of function mutations in either gene disrupt intracellular lipid trafficking and lead to a clinically heterogeneous phenotype that invariably includes neurological dysfunction and early death. The mechanism by which impaired lipid transport leads to neurodegeneration is poorly understood. Here we used mice with a conditional null allele to establish the timing and cell type that underlie neurodegeneration due to Npc1 deficiency. We show that global deletion

Adenoviral gene transfer of bone morphogenetic protein-7 enhances functional recovery after sciatic nerve injury in rats.

Bone morphogenetic proteins (BMPs), members of the transforming growth factor-β subfamily, function as instructive signals for neuronal lineage commitment and promote neuronal differentiation. However, the mechanism of BMP7 action in vivo after peripheral nerve injury is poorly understood. This study examines the efficacy of gene transfer of adenoviral (Ad) BMP7 on peripheral neuropathy. Transgene expression was found in both Ad-infected sciatic nerves and their respective remote neurons, indicating Ad transduction by a retrograde transport. After AdBMP7 infection to nerves, the sciatic nerves

Intersectin enhances huntingtin aggregation and neurodegeneration through activation of c-Jun-NH2-terminal kinase.

Huntingon's disease is a progressive neurodegenerative disease arising from expansion of a polyglutamine (polyQ) tract in the protein huntingtin (Htt) resulting in aggregation of mutant Htt into nuclear and/or cytosolic inclusions in neurons. Mutant Htt affects multiple processes including protein degradation, transcription, signal transduction, fast axonal transport and endocytosis [reviewed in Ross, C.A. and Poirier, M.A. (2005) Opinion: what is the role of protein aggregation in neurodegeneration? Nat. Rev. Mol. Cell. Biol., 6, 891-898]. Here, we report that the endocytic and signal transdu…

A preliminary neuropathological study of Japanese encephalitis in humans and a mouse model.

Japanese encephalitis virus is a mosquito-borne flavivirus that causes approximately 10000 deaths annually in Asia. After a brief viraemia, … rved in mouse brain tissue. In addition, beta-amyloid precursor protein staining indicated impaired axonal transport. Whether these findings are caused by viral replication in the vascular endothelium or the immune response merits further investigation.

AAV2-mediated ocular gene therapy for infantile neuronal ceroid lipofuscinosis.

Infantile neuronal ceroid lipofuscinosis (INCL) is a neurodegenerative disorder caused by mutations in the gene encoding the lysosomal enzym … cted in the brain following intravitreal injection. The brain activity is likely due to anterograde axonal transport along the optic tracts. Interestingly, the degree of neurodegeneration throughout the visual pathways of the brain was greatly reduced in AAV-treated INCL mice. Therefore, intravitreal AAV-mediated gene therapy has direct benefits to the eye and to …

Role of neurotrophins in diabetic neuropathy and treatment with nerve growth factors.

In rodent models of diabetes, there are expression deficits in nerve growth factor (NGF) and in mRNA for its high-affinity receptor, trkA, leading to decreased retrograde axonal transport of NGF and decreased support of NGF-dependent sensory neurons, with reduced expression of their neuropeptides, substance P and calcitonin gene-related peptide (CGRP). Treatment of diabetic rats with intensive insulin normalized these deficits, and treatment with exogenous NGF caused dose-related increases, giving levels of NGF and neuropeptides that were greater than those of controls. Neurotrophin-3 (NT-3) m…

Injection of doxorubicin into rabbit eyelid does not result in loss of facial motor neurons.

In both laboratory and clinical studies, injection of doxorubicin directly into the eyelid results in permanent muscle loss of the majority of fibers within treated eyelids. A first clinical trial of this technique in blepharospasm and hemifacial spasm patients has been performed. All patients who completed a full course of doxorubicin treatment showed a permanent decrease in eyelid strength, with over 50% of these patients requiring no further treatment. Doxorubicin is known to be carried by retrograde axonal transport to the brain and is a known neurotoxin. This raises the question of the ef…

Модель мыши для вирусов варицелла-зостеров.

После первичной инфекции вирусом варицелла-зостер (VZV) вирус создает скрытые инфекции у людей. Молекулярный патогенез опоздания VZV не вполне понятен, главным образом из-за отсутствия адекватной модели животных. Мы здесь сообщаем, что разработали модель мыши для инфекции VZV, которая включает кукурузную прививку мышей. Хотя у инфицированных животных не было никаких признаков заболевания, большинство животных не смогли устранить этот вирус раньше, чем инфекция. По PCR мы продемонстрировали, что в 33 дня после заражения (p.i.) вирусная ДНК все еще присутствовала более чем у 60% животных (14/21)

Совпадение в аннотации оригинала
Following primary infection with varicella-zoster virus (VZV), the virus establishes a latent infection in humans. The molecular pathogenesi … y other tissue by immunostaining. Our results suggest that VZV spreads in mice by both viraemia and axonal transport and establishes a non-productive (latent) infection.

A re-examination of the cerebellar projections from the gracile, main and external cuneate nuclei in the cat.

Cerebellar projections from the dorsal column and external cuneate nuclei in the cat have been studied by means of retrograde axonal transport of horseradish peroxidase. Localized injections covering the entire cerebellar cortex and nuclei show that the gracile nucleus has a weak projection only to the cortex of the anterior lobe, but that there is a conspicuous projection from the main cuneate nucleus to the cerebellum. Most of these fibres reach lobule V and the adjacent parts of lobules IV and VI, and there is also a heavy projection to the paramedian lobule. Some fibres reach lobule IX and…

A novel homozygous COX6A1 variant causes axonal charcot-marie-tooth disease, developmental delays and mitochondrial dysfunction.

Mitochondrial complex IV (cytochrome c oxidase, COX) is essential for oxidative phosphorylation, and pathogenic variants of COX-related genes, such as COX6A1, are associated with neuromuscular disorders. While recessive COX6A1 variants are linked to Charcot-Marie-Tooth disease (CMT), the phenotypic spectrum and molecular mechanism remain incompletely understood. Here we report a 2-year-4-month-old girl who presented with global developmental delay, axonal CMT disease, and elevated lactate levels. WES revealed a rare homozygous COX6A1 variant (NM_004373.4: c.329 A > T, p.110Leuext41) that is ab

Continuous Hypoxia Reduces Retinal Ganglion Cell Degeneration in a Mouse Model of Mitochondrial Optic Neuropathy.

PURPOSE: To test whether continuous hypoxia is neuroprotective to retinal ganglion cells (RGCs) in a mouse model of mitochondrial optic neuropathy. METHODS: RGC degeneration was assessed in genetically modified mice in which the floxed gene for the complex I subunit NDUFS4 is deleted from RGCs using Vlgut2-driven Cre recombinase. Beginning at postnatal day 25 (P25), Vglut2-Cre;ndufs4loxP/loxP mice and control littermates were housed under hypoxia (11% oxygen) or kept under normoxia (21% oxygen). Survival of RGC somas and axons was assessed at P60 and P90 via histological analysis of retinal f

RIM1/2 in retinal ganglion cells are required for the refinement of ipsilateral axons and eye-specific segregation.

Neural activity is crucial for the refinement of neuronal connections during development, but the contribution of synaptic release mechanisms is not known. In the mammalian retina, spontaneous neural activity controls the refinement of retinal projections to the dorsal lateral geniculate nucleus (dLGN) and the superior colliculus (SC) to form appropriate topographic and eye-specific maps. To evaluate the role of synaptic release, the rab-interacting molecules (RIMs), a family of active zone proteins that play a central role in calcium-triggered release, were conditionally ablated in a subset o

Astrocyte Structural and Molecular Response to Elevated Intraocular Pressure Occurs Rapidly and Precedes Axonal Tubulin Rearrangement within the Optic Nerve Head in a Rat Model.

Glaucomatous axon injury occurs at the level of the optic nerve head (ONH) in response to uncontrolled intraocular pressure (IOP). The temporal response of ONH astrocytes (glial cells responsible for axonal support) to elevated IOP remains unknown. Here, we evaluate the response of actin-based astrocyte extensions and integrin-based signaling within the ONH to 8 hours of IOP elevation in a rat model. IOP elevation of 60 mm Hg was achieved under isoflurane anesthesia using anterior chamber cannulation connected to a saline reservoir. ONH astrocytic extension orientation was significantly and re

Структурная оптимизация ретроградного ингибитора торговли людьми, который защищает клетки от инфекций полиомой и папилломавирусами человека.

Полиома и папилломавирусы человека - это неизмененные ДНК вирусы, которые вызывают серьезные патологии и смерть. В условиях иммуностатупсупрессии полиомавирус JC вызывает смертельное демиелинирующее заболевание, называемое прогрессивной многофукальной лейкоэнцефалопатией (ПМЛ), и полиомавирус BK является этиологическим агентом полиомавирусной нефропатии и геморрагического цитита. Человеческий папильомавирус типа 16, еще один неизмененный вирус ДНК связан с развитием рака в тканях, таких как шейная шейка матки и орофаринкс. В настоящее время не существует утвержденных лекарств или вакцин для ле

GSK3β is involved in the relief of mitochondria pausing in a Tau-dependent manner.

Mitochondrial trafficking deficits have been implicated in the pathogenesis of several neurological diseases, including Alzheimer's disease (AD). The Ser/Thre kinase GSK3β is believed to play a fundamental role in AD pathogenesis. Given that GSK3β substrates include Tau protein, here we studied the impact of GSK3β on mitochondrial trafficking and its dependence on Tau protein. Overexpression of GSK3β in neurons resulted in an increase in motile mitochondria, whereas a decrease in the activity of this kinase produced an increase in mitochondria pausing. These effects were dependent on Tau prote

Chapter 8 - Nanoparticles: Transport across the olfactory epithelium and application to the assessment of brain function in health and disease.

The exciting advances within nanotechnology are beginning to be harnessed by the medical field. Nanoparticles have been used for drug delivery into the brain and have been explored for imaging, sensing, and analytical purposes. The science of nanoparticles encompasses a vast array of biological, chemical, physical, and engineering research, different aspects of which are specifically addressed in each of the chapters of this volume. Nanomaterials such as nanospheres, nanotubes, nanowires, fullerene derivatives (buckyballs), and quantum dots (Qdots) are at the forefront of scientific attention,

[The affect of Erigeron Breviscapus (Vant.) Hand-Mazz on axoplasmic transport of optic nerve in rats with experimentally elevated intraocular pressure].

OBJECTIVE: To investigate whether Erigeron Breviscapus (Vant.) Hand-Mazz (EBHM) can improve the optic nerve axoplasmic transport in rats with experimentally elevated intraocular pressure (IOP). METHODS: Thirty healthy SD rats were used for the study, acute elevated IOP model in the right eye was built, then they were divided into three groups randomly: Group A (0 day group) included six rats for retinal ganglion cell (RGC) counting via left superior colliculus retrograde horse radish perokidase labeling; Group B, twelve rats divided into EBHM treatment group and control group (6 rats in each