Destruction Of Motor Neurons Research Articles

ИТОГИ ПИЛОТНОГО ПРОЕКТА ПО НЕОНАТАЛЬНОМУ СКРИНИНГУ СПИНАЛЬНОЙ МЫШЕЧНОЙ АТРОФИИ В САНКТ-ПЕТЕРБУРГЕ: ОРГАНИЗАЦИОННЫЕ, ДИАГНОСТИЧЕСКИЕ И КЛИНИЧЕСКИЕ АСПЕКТЫ

Spinal muscular atrophy (SMA) is one of the most frequent and severe hereditary diseases that leads to the destruction of motor neurons in the spinal cord and muscle weakness and is resulted from mutations in the SMN1 gene. The purpose of this research was to identify homo- and heterozygous mutations in the SMN1 gene in newborns. Materials and methods used: a multicenter prospective open continuous screening study of newborns at the age of 4 DoL (for full-term)/7 DoL (for preterm). The screening was carried out in Dec. 30, 2021-Nov. 17, 2022 on the basis of 21 obstetrics facilities located within the City of Saint Petersburg (Russia). Results: 36,140 participants (17,687 (49%) boys/18,453 (51%) girls) of the neonatal screening; 77 (0.21%) parents/caretakers have refused to participate. A technique for detecting homo- and heterozygous deletions in the SMN1 gene was developed based on rapid DNA extraction from dried blood spots followed by the real-time PCR. The project had identified 4 patients with SMA, two of whom had two and the other two had three copies of the SMN2 gene. The period of time needed to set the diagnosis ranged from 7th to 14th DoL. All of these patients have received the gene replacement therapy for a period of 3 to 5 months. There was a positive trend as a result of the therapy in all of the cases. 772 SMA carriers were also identified during the screening. 51% of their parents/caretakers have been followingly consulted on the possible risks of the disease. The frequency of SMA in the City of Saint Petersburg was 1 in 9035 newborns with a carrier frequency of 1 in 47. The sensitivity and specificity of the test were determined, which were 99.74% and 100%, respectively. Conclusion: SMA screening has been tested and put into practice. The conducted project of neonatal screening for SMA in the City of Saint Petersburg has demonstrated the readiness of its residents and the municipal healthcare system, the practitioners and organizers to this type of medical solution. The described developed methodology has demonstrated its effectiveness in terms of early detection of patients and carriers of this disease.

Nanozyme mediated SOD1 strategy linked to nanochaperone facilitate aggregation inhibition in amyotrophic lateral sclerosis.

Unlike natural enzymes, nanomaterial based ‘nanozyme’ offers higher stability and easy storage to address a steady function even in the extreme conditions of pH, temperature and molecular resistance to digestion from proteases. Nanozyme scavenging surplus reactive oxygen species (ROS) can serve as an effective tool to treat various neurodegenerative diseases. Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of the upper motor neuron and lower motor neuron leading to destruction of motor neurons and extra motor symptoms. Thus, loss/inefficiency of SOD1 enzymatic activity and its aggregation, both are known to be associated with ALS disease pathology. Here, nanoparticle (NP) functionalization strategy is used to develop a histidine (His) based superoxide dismutase-I (SOD1) therapeutic substitute with a dual role of nanozyme and nanochaperone activity. Zinc and Copper are an essential micronutrient of biological milieu in humans and act as an integral part of several enzymes active sites. His-functionalized nanozyme was found significant for scavenging excess ROS and targeting mitochondria with cytoprotective effect in the ALS model in-vitro. The nanochaperone role was characterized by its ability to reduce the aggregation of human apoSOD1WT and apoSOD1G93A mutant. In particular, a critical analysis of Amide I and III Raman band, specified to protein secondary structural elements suggested the decrease of a-helix and the early predominant b-sheets in human SOD1 in the absence of nanochaperone. But a reverse phenomenon was observed in the presence of nanochaperons. The dual role of nanozyme-nanochaperone provides a promising insightful into ALS pathology and may open new avenues for future therapeutics.

Spinal Muskuler Atrofisi Olan Çocuğun Hemşirelik Bakımı

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by defects in the survival motor neuron gene (SMN1). The disease, which progresses with the destruction of motor neurons in the anterior horn cells of the spinal cord, affects the voluntary muscles, causing symmetric weakness in the extremities and atrophy in the extremities and trunk. There are 5 clinical types classified according to the age of onset and severity of the disease. In recent years, there have been many developments in the treatment and care standards of the disease. In this review, SMA disease and nursing approach are discussed. Keywords: child, spinal muscular atrophy, nursing care

Sex-dependent effects of amyloid precursor-like protein 2 in the SOD1-G37R transgenic mouse model of MND

Motor neurone disease (MND) is a neurodegenerative disorder characterised by progressive destruction of motor neurons, muscle paralysis and death. The amyloid precursor protein (APP) is highly expressed in the central nervous system and has been shown to modulate disease outcomes in MND. APP is part of a gene family that includes the amyloid precursor-like protein 1 (APLP1) and 2 (APLP2) genes. In the present study, we investigated the role of APLP2 in MND through the examination of human spinal cord tissue and by crossing APLP2 knockout mice with the superoxide dismutase 1 (SOD1-G37R) transgenic mouse model of MND. We found the expression of APLP2 is elevated in the spinal cord from human cases of MND and that this feature of the human disease is reproduced in SOD1-G37R mice at the End-stage of their MND-like phenotype progression. APLP2 deletion in SOD1-G37R mice significantly delayed disease progression and increased the survival of female SOD1-G37R mice. Molecular and biochemical analysis showed female SOD1-G37R:APLP2−/− mice displayed improved innervation of the neuromuscular junction, ameliorated atrophy of muscle fibres with increased APP protein expression levels in the gastrocnemius muscle. These results indicate a sex-dependent role for APLP2 in mutant SOD1-mediated MND and further support the APP family as a potential target for further investigation into the cause and regulation of MND.

Amyotrophic Lateral Sclerosis, Resistance Training, Endurance Exercise, Tolerance, and Compliance

Amyotrophic Lateral Sclerosis, Resistance Training, Endurance Exercise, Tolerance, and Compliance

Neurofilament Heavy Chain and Tau Protein Are Not Elevated in Cerebrospinal Fluid of Adult Patients with Spinal Muscular Atrophy during Loading with Nusinersen.

Nusinersen is the first approved drug for the treatment of spinal muscular atrophy (SMA). Treatment of SMA with nusinersen is based on a fixed dosing regimen. For other motoneuron diseases, such as amyotrophic lateral sclerosis (ALS), biomarkers are available for clinical diagnostics; however, no such biomarkers have yet been found for SMA. Serum and cerebrospinal fluid (CSF) samples of 11 patients with adult SMA type 3 were prospectively collected and analyzed during loading with nusinersen. Neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase were investigated as potential biomarkers of motor neuron destruction. No significant pathological alterations in levels of neurofilament heavy chain, tau protein, or S100B protein were detected in the CSF or blood samples under baseline conditions or during loading with nusinersen. Neuron-specific enolase was marginally elevated in CSF and blood samples without significant alteration during treatment. In a mixed cohort of adult patients with SMA type 3, neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase do not serve as potential biomarkers during the loading phase of nusinersen. The slow progression rate of SMA type 3 may not lead to detectable elevation of levels of these common markers of axonal degradation.

Reinnervation of the diaphragm by the inferior laryngeal nerve to the phrenic nerve in ventilator-dependent tetraplegic patients with C3-5 damage.

The aim of this study was to evaluate the feasibility of unilateral diaphragmatic reinnervation in humans by the inferior laryngeal nerve. This pilot study included chronically ventilated tetraplegic patients with destruction of phrenic nerve motoneurons.Five patients were included. They all had a high level of tetraplegia, with phrenic nerve motor neuron destruction. They were highly dependent on ventilation, without any possibility of weaning. They did not have other chronic pathologies, especially laryngeal disease. They all had diaphragmatic explorations to diagnose the destruction of the motoneurons of the phrenic nerves and nasoendoscopy to be sure that they did not have laryngeal or pharyngeal disease. Then, surgical anastomosis of the right phrenic nerve was performed with the inferior laryngeal nerve, by a cervical approach. A laryngeal reinnervation was performed at the same time, using the ansa hypoglossi.One patient was excluded because of a functional phrenic nerve and one patient died 6 months after the surgery of a cardiac arrest. The remaining three patients were evaluated after the anastomosis every 6 months. They did not present any swallowing or vocal alterations. In these three patients, the diaphragmatic explorations showed that there was a recovery of the diaphragmatic electromyogram of the right and left hemidiaphragms after 1 year. Two patients had surgical diaphragmatic explorations for diaphragmatic pacing 18–24 months after the reinnervation with excellent results. At 36 months, none of the patients could restore their automatic ventilation.In conclusion, this study demonstrated that diaphragmatic reinnervation by the inferior laryngeal nerve is effective, without any vocal or swallowing complications.

Patient-derived olfactory mucosa for study of the non-neuronal contribution to amyotrophic lateral sclerosis pathology.

Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease which currently has no cure. Research using rodent ALS models transgenic for mutant superoxide dismutase 1 (SOD1) has implicated that glial–neuronal interactions play a major role in the destruction of motor neurons, but the generality of this mechanism is not clear as SOD1 mutations only account for less than 2% of all ALS cases. Recently, this hypothesis was backed up by observation of similar effects using astrocytes derived from post-mortem spinal cord tissue of ALS patients which did not carry SOD1 mutations. However, such necropsy samples may not be easy to obtain and may not always yield viable cell cultures. Here, we have analysed olfactory mucosa (OM) cells, which can be easily isolated from living ALS patients. Disease-specific changes observed when ALS OM cells were co-cultured with human spinal cord neurons included decreased neuronal viability, aberrant neuronal morphology and altered glial inflammatory responses. Our results show the potential of OM cells as new cell models for ALS.

Amyotrophic Lateral Sclerosis (ALS) about 2 Observations in the Neurology Department of the University Hospital of Cocody

Amyotrophic lateral sclerosis (ALS) is a rare but serious neurodegenerative disease characterized by progressive muscular paralysis without overall achievement of higher functions, resulting from motor neuron destruction. The present study reports two case...

Melittin ameliorates the inflammation of organs in an amyotrophic lateral sclerosis animal model.

Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disorder characterized by a selective loss of motor neurons in the spinal cord, brainstem, and motor cortex, leading to weakness of the limb and bulbar muscles. Although the immediate cause of death in ALS is the destruction of motor neurons, ALS is a multi-organ disease that also affects the lungs, spleen, and liver. Melittin is one of components of bee venom and has anti-neuroinflammatory effects in the spinal cord, as shown in an ALS animal model. To investigate the effects of melittin on inflammation in the lungs and spleen, we used hSOD1G93A transgenic mice that are mimic for ALS. Melittin treatment reduced the expression of inflammatory proteins, including Iba-1 and CD14 by 1.9- and 1.3-fold (p<0.05), respectively, in the lungs of symptomatic hSOD1G93A transgenic mice. In the spleen, the expression of CD14 and COX2 that are related to inflammation were decreased by 1.4 fold (p<0.05) and cell survival proteins such as pERK and Bcl2 were increased by 1.3- and 1.5-fold (p<0.05) in the melittin-treated hSOD1G93A transgenic mice. These findings suggest that melittin could be a candidate to regulate the immune system in organs affected by ALS.

Sulfated polysaccharide of Caesalpinia ferrea inhibits herpes simplex virus and poliovirus

Herpes simplex virus (HSV) is one of the most regular human pathogens, being a public health problem, and causal agent of several diseases. Poliovirus (PV) is an enteric virus and about 1% of infected individuals develop paralytic poliomyelitis due to viral invasion of the central nervous system and destruction of motor neurons. This work evaluated the activity of a sulfated polysaccharide of Caesalpinia ferrea (SPLCf) in HSV and PV replication. The antiviral effect of SPLCf at varying concentrations was tested by plaque assay under several protocols, such as time-of-addition, adsorption and penetration inhibition and virucidal. Syntheses of viral protein and nucleic acid were also monitored by the immunofluorescence assay and PCR. The SPLCf inhibited virus adsorption and steps after penetration, and inhibited the synthesis of viral protein. Virucidal effect was also shown and nucleic acid synthesis was concurrent with positive results. Our findings suggested that the substance with low toxicity represent a potential viral inhibitor.

Receptor modification as a therapeutic approach against viral diseases.

Poliovirus causes flaccid paralysis through the destruction of motor neurons in the CNS. Susceptibility to its infection is mainly due to the interaction in between the surface capsid proteins and its receptors on the host cell surface, important for binding, penetration and other necessary events during early infection. Receptor modification is a new approach to treat viral diseases by the modification of target proteins structure. Binding domains are modified in an effective way to make it difficult for the virus to recognize it. In this study, tolerant and intolerant induced mutations in the poliovirus receptor, VP1 and VP2 were identified and substituted in the seed sequence to get the modified versions. Substitutions causing changes in initial folding were short listed and further analyzed for high level folding, physiochemical properties and interactions. Highest RMSD values were observed in between the seed and the mutant K90F (3.265 Å) and Q130W (3.270Å) respectively. The proposed substitutions were found to have low functional impact and thus can be further tested and validated by the experimental researchers. Interactions analyses proved most of the substitutions having decreased affinity for both the VP1 and VP2 and thus are of significant importance against poliovirus. This study will play an important role for bridging computational biology to other fields of applied biology and also will provide an insight to develop resistance against viral diseases. It is also expected that same approach can also be applicable against other viruses like HCV, HIV and other in near future.

Amyotrophic Lateral Sclerosis – Clinical Features, Pathophysiology and Management

Amyotrophic lateral sclerosis (ALS), first described by Jean-Martin Charcot 145 years ago, is an age-related neurodegenerative disorder that leads to destruction of motor neurons. The disease begins focally in the central nervous system then spreads inexorably. The clinical diagnosis, defined by progressive upper and lower motor neuron findings, is confirmed by electromyogram. Additional testing excludes other conditions. The disease is heterogeneous, but most patients die of progressive weakness and respiratory failure less than 3 years from symptom onset. Like other neurodegenerative diseases, ALS is thought to have genetic and environmental causes. Five to 10 % of cases are inherited. Genetic factors, age, tobacco use and athleticism may contribute to sporadic ALS, but major causes are unidentified for most patients. Complex pathophysiological processes, including mitochondrial dysfunction, aggregation of misfolded protein, oxidative stress, excitotoxicity, inflammation and apoptosis, involve both motor neurons and surrounding glial cells. There is clinical and pathological overlap with other neurodegenerative diseases, particularly frontotemporal dementia. One medication, riluzole, which was approved in 1996, prolongs survival by several months. Numerous ensuing clinical trials have been negative. Researchers currently aim to slow disease progression by targeting known pathophysiological pathways. Approaches under examination are directed at muscle protein, energetic balance, cell replacement and protein aggregation. Until the causes and more robust neuroprotective agents are identified, symptomatic therapies can help improve expectancy and quality of life. Palliative care ensures dignity in advanced stages.

Induced Differentiation of Neural Stem Cells of Astrocytic Origin to Motor Neurons in the Rat

Destruction of the motor neurons will lead to loss of innervation of the somatic muscle, which has long been considered an illness with no remedy. The only possible treatment is to substitute the injured motor neurons by neurons differentiated from stem cells. It has been recently reported that embryonic stems cells can be induced to differentiate to motor neurons. However, the use of embryonic stem cells has innate problems. The ideal source of motor neurons should be the cells from the patients themselves, which have the potential to be induced to motor neurons. Our previous study demonstrated that mature astrocyte has the potential of being dedifferentiated to neural stem cell. The present study was aimed to investigate if the neural stem cells of astrocytic origin can be induced to motor neurons. The results demonstrated that neural stem cells of astrocytic origin could be induced to differentiate into motor neurons and their progenitor cells with rich harvest. Further, it has been reported that astrocytes can be readily obtained via biopsy from the cerebral cortex of the patient, rendering autologous transplantation possible. In conclusion, matured astrocytes can be induced to motor neurons and be autologously transplanted to patients suffering from motor neuron destruction.

Riluzole, Neuroprotection and Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease of the human motor system. Aetiological mechanisms implicated in the development of ALS have been linked to the glutamatergic neurotransmitter system, with destruction of motor neurons triggered through excessive activation of glutamate receptors at the synaptic cleft. This 'excitotoxicity' theory of ALS gave rise to the development of therapeutic approaches and ultimately clinical trials involving riluzole, initially thought to act solely as an inhibitor of glutamate release. Subsequent effects of riluzole have been postulated to include indirect antagonism of glutamate receptors, in addition to inactivation of neuronal voltage-gated Na+ channels. Riluzole remains the only disease-modifying therapy available to patients with ALS. Despite having been clinically available since the mid-1990 s, the in vivo pharmacological targets of riluzole have been poorly defined. An improved understanding concerning the potential neuroprotective mechanisms of riluzole may unearth pathophysiological processes that mediate neurodegeneration in ALS. The present review summarises the known chemical and pharmacological properties of riluzole. The failure of other putative neuroprotective therapies to demonstrate positive treatment outcomes in this intractable disease will be reviewed. Finally, the hypothesis that Na+ conductances may be involved in the processes of neuronal and axonal degeneration in ALS will be explored.

Structural and biophysical properties of metal-free pathogenic SOD1 mutants A4V and G93A

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease characterized by the destruction of motor neurons in the spinal cord and brain. A subset of ALS cases are linked to dominant mutations in copper–zinc superoxide dismutase (SOD1). The pathogenic SOD1 variants A4V and G93A have been the foci of multiple studies aimed at understanding the molecular basis for SOD1-linked ALS. The A4V variant is responsible for the majority of familial ALS cases in North America, causing rapidly progressing paralysis once symptoms begin and the G93A SOD1 variant is overexpressed in often studied murine models of the disease. Here we report the three-dimensional structures of metal-free A4V and of metal-bound and metal-free G93A SOD1. In the metal-free structures, the metal-binding loop elements are observed to be severely disordered, suggesting that these variants may share mechanisms of aggregation proposed previously for other pathogenic SOD1 proteins.

Mutations in the copper- and zinc-containing superoxide dismutase gene are associated with "Lou Gehrig's disease".

Recent genetic analyses of patients with a familial, chromosome 21-linked form of amyotrophic lateral sclerosis (ALS), sometimes called Lou Gehrig's disease, suggest that mutations in the cytosolic copper/zinc superoxide dismutase (SOD1) gene may be involved in development of the disease. Although no functional disturbance of SOD1 activity has yet been identified, altered free radical protection may contribute to the destruction of motor neurons. The role of antioxidant status needs to be investigated as a possible preventive and therapeutic intervention for ALS.

Sensory involvement in the SOD1-G93A mouse model of amyotrophic lateral sclerosis

A subset of patients of amyotrophic lateral sclerosis (ALS) present with mutation of Cu/Zn superoxide dismutase 1 (SOD1), and such mutants caused an ALS- like disorder when expressed in rodents. These findings implicated SOD1 in ALS pathogenesis and made the transgenic animals a widely used ALS model. However, previous studies of these animals have focused largely on motor neuron damage. We report herein that the spinal cords of mice expressing a human SOD1 mutant (hSOD1-G93A), besides showing typical destruction of motor neurons and axons, exhibit significant damage in the sensory system, including Wallerian-like degeneration in axons of dorsal root and dorsal funiculus, and mitochondrial damage in dorsal root ganglia neurons. Thus, hSOD1-G93A mutation causes both motor and sensory neuropathies, and as such the disease developed in the transgenic mice very closely resembles human ALS.

Experimental Reovirus-Induced Acute Flaccid Paralysis and Spinal Motor Neuron Cell Death

Acute flaccid paralysis (AFP) describes the loss of motor function in 1 or more limbs commonly associated with viral infection and destruction of motor neurons in the anterior horns of the spinal cord. Therapy is limited, and the development of effective treatments is hampered by a lack of experimental models. Reovirus infection of neonatal mice provides a model for the study of CNS viral infection pathogenesis. Injection of the Reovirus serot Type 3 strains Abney (T3A) or Dearing (T3D) into the hindlimb of 1-day-old mice resulted in the development of AFP in more than 90% of infected mice. Acute flaccid paralysis began in the ipsilateral hindlimb at 8 to 10 days postinfection and progressed to paraplegia 24 hours later. Paralysis correlated with injury, neuron loss, and spread of viral antigen first to the ipsilateral and then to the contralateral anterior horns. As demonstrated by the activation of caspase 3 and its colocalization with viral antigen in the anterior horn and concomitant cleavage of poly-(adenosine diphosphate-ribose) polymerase, AFP was associated with apoptosis. Calpain activity and inducible nitric oxide synthase expression were both elevated in the spinal cords of paralyzed animals. This study represents the first detailed characterization of a novel and highly efficient experimental model of virus-induced AFP that will facilitate evaluation of therapeutic strategies targeting virus-induced paralysis.

T cells in amyotrophic lateral sclerosis

The inflammatory process in ALS involves infiltration of T cells and activation of antigen presenting cells co-localizing with motor neuron damage in the brain and spinal cord. The role of T cells in the pathogenic process is not settled. T cells may damage motor neurons by cell-cell contact or cytokine secretion, or contribute indirectly to motor neuron damage through activation of microglia and macrophages. Alternatively, T cell infiltration may be an epiphenomenon related to clearance of dead motor neurons. Lessons from animal models of neuroinflammation and neurodegeneration have shown that T cell responses can be neuroprotective or even enhance neurogenesis. Therefore, it is possible that T cells can be induced to slow motor neuron destruction and facilitate repair in ALS. The T cell modulating drug glatiramer acetate has shown promising results in animal models, and is being currently investigated in a phase II trial in ALS. This paper reviews the evidence for T cells as pathogenic players and therapeutic targets in ALS.