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Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons.

Reactive oxygen species (ROS) contribute to tissue damage and remodelling mediated by the inflammatory response after injury. Here we show that ROS, which promote axonal dieback and degeneration after injury, are also required for axonal regeneration and functional recovery after spinal injury. We find that ROS production in the injured sciatic nerve and dorsal root ganglia requires CX3CR1-dependent recruitment of inflammatory cells. Next, exosomes containing functional NADPH oxidase 2 complexes are released from macrophages and incorporated into injured axons via endocytosis. Once in axonal e

Increased production of ubiquitin mRNA in motor neurons after axotomy.

Ubiquitin targets proteins for attack by certain proteolytic enzymes, but the ubiquitinated cytoplasmic inclusions seen in some chronic neurodegenerative diseases may indicate the occurrence of reparative rather than destructive metabolic events. We have examined the production of ubiquitin in motor neurons of the rat's left hypoglossal nucleus after transection of their axons in circumstances that favour or prevent axonal regeneration. One week after axotomy, in situ hybridization with a radiolabelled cRNA probe revealed a twofold increase in the ubiquitin mRNA content of neurons with regener

Absence of the axon initial segment in sensory neuron enhances resistance to amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Proteasome dysfunction in ALS is considered to cause the accumulation of protein aggregates, which leads to motor neuron degeneration; however, the resilience of motor neurons to ALS pathology might be impaired long before the appearance of protein aggregates. Intriguingly, sensory dorsal root ganglion (DRG) neurons are not susceptible to ALS pathology despite their processes coexisting with axons of motor neurons in the same spinal nerves. Both DRG neurons and motor neurons

A nerve growth factor-induced retrograde survival signal mediated by mechanisms downstream of TrkA.

Considerable evidence suggests that mammalian neurons are always poised to destroy themselves by apoptosis but are blocked by retrograde survival signals triggered in their axon terminals by neurotrophic factors secreted by the target cells they innervate. Studies with nerve growth factor (NGF) and its receptor, TrkA, form the basis of the prevalent theory of retrograde signaling. According to this theory, retrograde survival signals travel to the cell bodies in the form of endosomes produced at the axon terminals with internalized NGF in their lumens bound to phosphorylated TrkA in their memb

Early astrocyte redistribution in the optic nerve precedes axonopathy in the DBA/2J mouse model of glaucoma.

Glaucoma challenges the survival of retinal ganglion cell axons in the optic nerve through processes dependent on both aging and ocular pressure. Relevant stressors likely include complex interplay between axons and astrocytes, both in the retina and optic nerve. In the DBA/2J mouse model of pigmentary glaucoma, early progression involves axonopathy characterized by loss of functional transport prior to outright degeneration. Here we describe novel features of early pathogenesis in the DBA/2J nerve. With age the cross-sectional area of the nerve increases; this is associated generally with dim

Mitochondrial mislocalization underlies Abeta42-induced neuronal dysfunction in a Drosophila model of Alzheimer's disease.

The amyloid-beta 42 (Abeta42) is thought to play a central role in the pathogenesis of Alzheimer's disease (AD). However, the molecular mech … evere mitochondrial damage or neurodegeneration. In contrast, organization of microtubule or global axonal transport was not significantly altered at this stage. Abeta42-induced behavioral defects were exacerbated by genetic reductions in mitochondrial transport, and were modulated by cAMP levels and PKA activity. Levels of putative PKA substrate phosphoproteins w …

Heterogeneous intracellular trafficking dynamics of brain-derived neurotrophic factor complexes in the neuronal soma revealed by single quantum dot tracking.

Accumulating evidence underscores the importance of ligand-receptor dynamics in shaping cellular signaling. In the nervous system, growth fa … heterogeneous nature of neuronal soma trafficking dynamics contrasts the reported linear nature of axonal transport data and calls for models that surpass our generally limited notions of nuclear-directed transport in the soma. QD-ligand probes are poised to provide understanding of how the molecular mechanisms underlying intracellular ligand-receptor trafficking …

Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling.

In neurons, microtubules form a dense array within axons, and the stability and function of this microtubule network is modulated by neurofi … rotein becomes instable which then results in destabilization of axonal microtubules and defects in axonal transport, in particular in motoneurons. Depletion of neurofilament increases the number and regrowth of microtubules in pmn mutant motoneurons and restores axon elongation. This effect is mediated by interaction of neurofilament with the stathmin complex. Ac …

Decoding RNA splicing pathology: Alternative splicing in amyotrophic lateral sclerosis and its therapeutic potential.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron loss, leading to muscle weaknes … Mutant SOD1 contributes via mitochondrial dysfunction, endoplasmic reticulum stress, and disrupted axonal transport. Therapeutic strategies targeting these mechanisms are advancing rapidly. Gene replacement therapy, which restores STMN2 expression, and antisense oligonucleotides (ASOs) targeting mutant transcripts show promise in preclinical and early clinical st …

Progressive Optic Neuropathy in Hydrocephalic Ccdc13 Mutant Mice Caused by Impaired Axoplasmic Transport at the Optic Nerve Head.

PURPOSE: Optic nerve head (ONH) atrophy is frequently associated with hydrocephalic conditions. Cerebrospinal fluid (CSF)-containing meninge … of axonal ultrastructure and deposition of unphosphorylated neurofilament heavy chain. Anterograde axonal transport was also hampered. Retinal ganglion cell (RGC) function was compromised as early as postnatal day 21 (P21), along with reduced neurofilament heavy chain expression. Optic neuropathy caused by disruption of Ccd13 was non-cell autonomous, stemming fro …

A revised nomenclature for the lemur family of protein kinases.

The lemur family of protein kinases has gained much interest in recent years as they are involved in a variety of cellular processes including regulation of axonal transport and endosomal trafficking, modulation of synaptic functions, memory and learning, and they are centrally placed in several intracellular signalling pathways. Numerous studies have also implicated role of the lemur kinases in the development and progression of a wide range of cancers, cystic fibrosis, and neurodegenerative diseases. However, parallel discoveries and inaccurate prediction of their kinase activity have result…

Разработка доклинической платформы человека для идентификации нетронутых охранных соединений.

Множественный склероз (MS) является наиболее распространенным воспалительным и демиелинизирующим заболеванием, влияющим на центральную нервную систему (КНС). В то время как иммуномодилизующие препараты могут предотвратить новые повреждения, реагируя на лимфоцитную активность, лечение не зависящих от рецидива заболеваний по-прежнему сопряжено с трудностями. Продолжительная воспаление CNS, приводящее к аксоновому и нейронному повреждению, а также к отсутствию компенсационных механизмов, таких, как пластичность мозга и воспаление, стимулирует развитие болезни. Таким образом, срочно необходимо иде

Совпадение в аннотации оригинала
Multiple sclerosis (MS) is the most common inflammatory and demyelinating disease affecting the central nervous system (CNS). While immune-m … involve reducing mitochondrial reactive oxygen species (ROS) production via PGC-1α and stabilizing axonal transport through GSK3β phosphorylation. Minocycline mainly impacted glutathione metabolism. In the cuprizone model, both compounds displayed neuroprotective effects but did not reduce demyelination or oligodendroglial loss. In summary, our findings demonstra …

Role of oxidative stress in rabies virus infection.

Recent studies in an experimental model of rabies indicated that there are major structural changes in the brain involving neuronal processes that are associated with severe clinical disease. Cultured adult mouse dorsal root ganglion (DRG) neurons are a good in vitro model for studying the mechanisms involved in rabies virus-induced degeneration of neurites (axons) because, unlike other neuronal cell types, these neurons are fairly permissive to rabies virus infection. DRG neurons infected with the challenge virus standard-11 (CVS) strain of rabies virus show axonal swellings and immunostainin

Neuroaxonal pathology in Creutzfeldt-Jakob disease.

Neuroaxonal pathology has met little attention in transmissible spongiform encephalopathies. In brains of a series of 39 consecutive Creutzf … a frequent and important part of brain lesioning in CJD, probably reflecting profound impairment of axonal transport.

Developmental and Age-Related RAB-3 phenotypes in a C. elegans Tauopathy Model.

Tauopathies are neurodegenerative diseases characterized by aggregation of Tau into neurofibrillary tangles. Elucidation of cellular phenomena occurring in degenerative states will be important for long-term mitigation strategies. Here we show two phenotypes involving the synaptic vesicle protein RAB-3 in a Caenorhabditis elegans TauV337M model: a developmental reduction of RAB-3 and an age-related mislocalization in motor axons. We further show that the developmental reduction of RAB-3 is not due to changes in transcriptional expression. We suggest axonal transport and/or synaptic vesicle rec…

Localization of zinc-enriched neurons in the mouse peripheral sympathetic system.

Growing evidence supports the notion that zinc ions located in the synaptic vesicles of zinc-enriched neurons (ZEN) play important physiological roles and are involved in certain pathological changes in the central nervous system. Here we present data revealing the distribution of zinc ions and the co-localization of zinc transporter 3 (ZnT3) and tyrosine hydroxylase (TH) in crush-operated sciatic nerves and lumbar sympathetic ganglia of mice, using zinc selenide autometallography (ZnSe(AMG)) and ZnT3 immunofluorescence combined with confocal scanning microscopy, respectively. Six hours after

Progressive axonopathy: an inherited neuropathy of boxer dogs. Quantitative and morphometric analysis of the peripheral nerve lesion.

Previous studies have described and illustrated the lesions in the peripheral nerves in progressive axonopathy, an inherited neuropathy of B … numbers of regenerating clusters at most stages. It is suggested that in progressive axonopathy an axonal transport failure may occur in the roots leading to the axonal swellings, as a result of which a developmental hypoplasia occurs in the more distal, larger diameter fibres. The prominent, but unevenly distributed, myelin sheath changes indicate a severe distu …

Huntington's disease: from huntingtin function and dysfunction to therapeutic strategies.

Huntington's disease (HD) is a neurodegenerative disorder that usually starts in middle age and is characterized by involuntary movements (chorea), personality changes and dementia, leading to death within 10-20 years. The defective gene in HD contains a trinucleotide CAG repeat expansion within its coding region that expresses a polyglutamine repeat in the protein huntingtin. Together with the characteristic formation of aggregates in HD, aberrant protein interactions and several post-translational modifications affect huntingtin during disease progression and lead to the dysfunction and deat

CMT2 and distal hereditary motor neuropathy associated with VRK1 variants: Case series.

Axonal Charcot-Marie-Tooth disease (CMT2) and distal hereditary motor neuropathy (dHMN) are associated with a heterogeneous group of genes encoding proteins that are involved in axonal transport, control of RNA metabolism, mitochondrial dynamics and DNA repair. VRK1 (vaccinia-related kinase 1) is a serine/threonine kinase which is widely expressed in human tissue and plays a role in RNA maturation and processing and in DNA damage response. Variants of VRK1 have been associated with neurodevelopmental and neuromuscular disorders including pontocerebellar hypoplasia, motor neuron disorders and d…