Multifaceted superoxide dismutase 1 expression in amyotrophic lateral sclerosis patients:a rare occurrence?

Amyotrophic lateral sclerosis(ALS)is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex,brainstem,and spinal cord.While the typical clinical phenotype of ALS involves both upper and lower motor neurons,human and animal studies over the years have highlighted the potential spread to other motor and non-motor regions,expanding the phenotype of ALS.Although superoxide dismutase 1(SOD1)mutations represent a minority of ALS cases,the SOD1 gene remains a milestone in ALS research as it represents the first genetic target for personalized therapies.Despite numerous single case reports or case series exhibiting extramotor symptoms in patients with ALS mutations in SOD1(SOD1-ALS),no studies have comprehensively explored the full spectrum of extramotor neurological manifestations in this subpopulation.In this narrative review,we analyze and discuss the available literature on extrapyramidal and non-motor features during SOD1-ALS.The multifaceted expression of SOD1 could deepen our understanding of the pathogenic mechanisms,pointing towards a multidisciplinary approach for affected patients in light of new therapeutic strategies for SOD1-ALS.

Skeletal muscle as a molecular and cellular biomarker of disease progression in amyotrophic lateral sclerosis:a narrative review

Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary target.Although progressive weakness is a hallmark feature of amyotrophic lateral sclerosis,there is considerable heterogeneity,including clinical presentation,progression,and the underlying triggers for disease initiation.Based on longitudinal studies with families harboring amyotrophic lateral sclerosis-associated gene mutations,it has become apparent that overt disease is preceded by a prodromal phase,possibly in years,where compensatory mechanisms delay symptom onset.Since 85-90%of amyotrophic lateral sclerosis is sporadic,there is a strong need for identifying biomarkers that can detect this prodromal phase as motor neurons have limited capacity for regeneration.Current Food and Drug Administration-approved therapies work by slowing the degenerative process and are most effective early in the disease.Skeletal muscle,including the neuromuscular junction,manifests abnormalities at the earliest stages of the disease,before motor neuron loss,making it a promising source for identifying biomarkers of the prodromal phase.The accessibility of muscle through biopsy provides a lens into the distal motor system at earlier stages and in real time.The advent of“omics”technology has led to the identification of numerous dysregulated molecules in amyotrophic lateral sclerosis muscle,ranging from coding and non-coding RNAs to proteins and metabolites.This technology has opened the door for identifying biomarkers of disease activity and providing insight into disease mechanisms.A major challenge is correlating the myriad of dysregulated molecules with clinical or histological progression and understanding their relevance to presymptomatic phases of disease.There are two major goals of this review.The first is to summarize some of the biomarkers identified in human amyotrophic lateral sclerosis muscle that have a clinicopathological correlation with disease activity,evidence of a similar dysregulation in the SOD1G93A mouse during presymptomatic stages,and evidence of progressive change during disease progression.The second goal is to review the molecular pathways these biomarkers reflect and their potential role in mitigating or promoting disease progression,and as such,their potential as therapeutic targets in amyotrophic lateral sclerosis.

The pathogenic mechanism of TAR DNA-binding protein 43(TDP-43)in amyotrophic lateral sclerosis

The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex,basal ganglia,brainstem,and spinal cord,and commonly involves the muscles of the upper and/or lower extremities,and the muscles of the bulbar and/or respiratory regions.However,as the disease progresses,it affects the adjacent body regions,leading to generalized muscle weakness,occasionally along with memory,cognitive,behavioral,and language impairments;respiratory dysfunction occurs at the final stage of the disease.The disease has a complicated pathophysiology and currently,only riluzole,edaravone,and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized countries.The TAR DNA-binding protein 43 inclusions are observed in 97%of those diagnosed with amyotrophic lateral sclerosis.This review provides a preliminary overview of the potential effects of TAR DNAbinding protein 43 in the pathogenesis of amyotrophic lateral sclerosis,including the abnormalities in nucleoplasmic transport,RNA function,post-translational modification,liquid-liquid phase separation,stress granules,mitochondrial dysfunction,oxidative stress,axonal transport,protein quality control system,and non-cellular autonomous functions(e.g.,glial cell functions and prion-like propagation).

OSMR is a potential driver of inflammation in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a neurodegenerative disease,and the molecular mechanism underlying its pathology remains poorly understood.However,inflammation is known to play an important role in the development of this condition.To identify driver genes that affect the inflammatory response in amyotrophic lateral sclerosis,as well as potential treatment targets,it is crucial to analyze brain tissue samples from patients with both sporadic amyotrophic lateral sclerosis and C9orf72-related amyotrophic lateral sclerosis.Therefore,in this study we used a network-driven gene analysis tool,NetBID2.0,which is based on SJARACNe,a scalable algorithm for the reconstruction of accurate cellular networks,to experimentally analyze sequencing data from patients with sporadic amyotrophic lateral sclerosis.The results showed that the OSMR gene is pathogenic in amyotrophic lateral sclerosis and participates in the progression of amyotrophic lateral sclerosis by mediating the neuroinflammatory response.Furthermore,there were differences in OSMR activity and expression between patients with sporadic amyotrophic lateral sclerosis and those with C9orf72-related amyotrophic lateral sclerosis.These findings suggest that OSMR may be a diagnostic and prognostic marker for amyotrophic lateral sclerosis.

Circulating proteomic biomarkers for diagnosing sporadic amyotrophic lateral sclerosis:a cross-sectional study

Biomarke rs are required for the early detection,prognosis prediction,and monitoring of amyotrophic lateral sclerosis,a progressive disease.Proteomics is an unbiased and quantitative method that can be used to detect neurochemical signatures to aid in the identification of candidate biomarke rs.In this study,we used a label-free quantitative proteomics approach to screen for substantially differentially regulated proteins in ten patients with sporadic amyotrophic lateral scle rosis compared with five healthy controls.Su bstantial upregulation of serum proteins related to multiple functional clusters was observed in patients with spo radic amyotrophic lateral sclerosis.Potential biomarke rs were selected based on functionality and expression specificity.To validate the proteomics profiles,blood samples from an additional cohort comprising 100 patients with sporadic amyotrophic lateral sclerosis and 100 healthy controls were subjected to enzyme-linked immunosorbent assay.Eight substantially upregulated serum proteins in patients with spora dic amyotrophic lateral sclerosis were selected,of which the cathelicidin-related antimicrobial peptide demonstrated the best discriminative ability between patients with sporadic amyotrophic lateral sclerosis and healthy controls(area under the curve[AUC]=0.713,P<0.0001).To further enhance diagnostic accuracy,a multi-protein combined discriminant algorithm was developed incorporating five proteins(hemoglobin beta,cathelicidin-related antimicrobial peptide,talin-1,zyxin,and translationally-controlled tumor protein).The algo rithm achieved an AUC of 0.811 and a P-value of<0.0001,resulting in 79%sensitivity and 71%specificity for the diagnosis of sporadic amyotrophic lateral scle rosis.Subsequently,the ability of candidate biomarkers to discriminate between early-stage amyotrophic lateral sclerosis patients and controls,as well as patients with different disease severities,was examined.A two-protein panel comprising talin-1 and translationally-controlled tumor protein effectively distinguished early-stage amyotrophic lateral sclerosis patients from controls(AUC=0.766,P<0.0001).Moreove r,the expression of three proteins(FK506 binding protein 1A,cathelicidin-related antimicrobial peptide,and hemoglobin beta-1)was found to increase with disease progression.The proteomic signatures developed in this study may help facilitate early diagnosis and monitor the progression of sporadic amyotrophic lateral sclerosis when used in co mbination with curre nt clinical-based parameters.

NRF2 signaling cascade in amyotrophic lateral sclerosis:bridging the gap between promise and reality

Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons.Symptoms include muscle weakness and atrophy,spasticity,and progressive paralysis.Currently,there is no treatment to reverse damage to motor neurons and cure amyotrophic lateral sclerosis.The only two treatments actually approved,riluzole and edaravone,have shown mitigated beneficial effects.The difficulty to find a cure lies in the complexity and multifaceted pattern of amyotrophic lateral sclerosis pathogenesis.Among mechanisms,abnormal RNA metabolism,nucleocytoplasmic transport defects,accumulation of unfolded protein,and mitochondrial dysfunction would in fine induce oxidative damage and vice versa.A potent therapeutic strategy will be to find molecules that break this vicious circle.Sharpening the nuclear factor erythroid-2 related factor 2 signaling may fulfill this objective since nuclear factor erythroid-2 related factor 2 has a multitarget profile controlling antioxidant defense,mitochondrial functioning,and inflammation.We here discuss the interest of developing nuclear factor erythroid-2 related factor 2-based therapy in regard to the pathophysiological mechanisms and we provide a general overview of the attempted clinical assays in amyotrophic lateral sclerosis.

Blood diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited.The principal pathological alterations of the disease include the selective degeneration of motor neurons in the brain,brainstem,and spinal cord,as well as abnormal protein deposition in the cytoplasm of neurons and glial cells.The biological markers under extensive scrutiny are predominantly located in the cerebrospinal fluid,blood,and even urine.Among these biomarke rs,neurofilament proteins and glial fibrillary acidic protein most accurately reflect the pathologic changes in the central nervous system,while creatinine and creatine kinase mainly indicate pathological alterations in the peripheral nerves and muscles.Neurofilament light chain levels serve as an indicator of neuronal axonal injury that remain stable throughout disease progression and are a promising diagnostic and prognostic biomarker with high specificity and sensitivity.However,there are challenges in using neurofilament light chain to diffe rentiate amyotrophic lateral sclerosis from other central nervous system diseases with axonal injury.Glial fibrillary acidic protein predominantly reflects the degree of neuronal demyelination and is linked to non-motor symptoms of amyotrophic lateral sclerosis such as cognitive impairment,oxygen saturation,and the glomerular filtration rate.TAR DNA-binding protein 43,a pathological protein associated with amyotrophic lateral sclerosis,is emerging as a promising biomarker,particularly with advancements in exosome-related research.Evidence is currently lacking for the value of creatinine and creatine kinase as diagnostic markers;however,they show potential in predicting disease prognosis.Despite the vigorous progress made in the identification of amyotrophic lateral sclerosis biomarkers in recent years,the quest for definitive diagnostic and prognostic biomarke rs remains a formidable challenge.This review summarizes the latest research achievements concerning blood biomarkers in amyotrophic lateral sclerosis that can provide a more direct basis for the differential diagnosis and prognostic assessment of the disease beyond a reliance on clinical manifestations and electromyography findings.

The burden of upper motor neuron involvement is correlated with the bilateral limb involvement interval in patients with amyotrophic lateral sclerosis:a retrospective observational study

Amyotrophic lateral sclerosis is a rare neurodegenerative disease characterized by the involvement of both upper and lower motor neurons.Early bilateral limb involvement significantly affects patients'daily lives and may lead them to be confined to bed.However,the effect of upper and lower motor neuron impairment and other risk factors on bilateral limb involvement is unclear.To address this issue,we retrospectively collected data from 586 amyotrophic lateral sclerosis patients with limb onset diagnosed at Peking University Third Hospital between January 2020 and May 2022.A univariate analysis revealed no significant differences in the time intervals of spread in different directions between individuals with upper motor neuron-dominant amyotrophic lateral sclerosis and those with classic amyotrophic lateral sclerosis.We used causal directed acyclic graphs for risk factor determination and Cox proportional hazards models to investigate the association between the duration of bilateral limb involvement and clinical baseline characteristics in amyotrophic lateral sclerosis patients.Multiple factor analyses revealed that higher upper motor neuron scores(hazard ratio[HR]=1.05,95%confidence interval[CI]=1.01–1.09,P=0.018),onset in the left limb(HR=0.72,95%CI=0.58–0.89,P=0.002),and a horizontal pattern of progression(HR=0.46,95%CI=0.37–0.58,P<0.001)were risk factors for a shorter interval until bilateral limb involvement.The results demonstrated that a greater degree of upper motor neuron involvement might cause contralateral limb involvement to progress more quickly in limb-onset amyotrophic lateral sclerosis patients.These findings may improve the management of amyotrophic lateral sclerosis patients with limb onset and the prediction of patient prognosis.

Safety of intrathecal injection of Wharton's jellyderived mesenchymal stem cells in amyotrophic lateral sclerosis therapy

Animal experiments have confirmed that mesenchymal stem cells can inhibit motor neuron apoptosis and inflammatory factor expression and increase neurotrophic factor expression. Therefore, mesenchymal stem cells have been shown to exhibit prospects in the treatment of amyotrophic lateral sclerosis. However, the safety of their clinical application needs to be validated. To investigate the safety of intrathecal injection of Wharton's jelly-derived mesenchymal stem cells in amyotrophic lateral sclerosis therapy, 43 patients(16 females and 27 males, mean age of 57.3 years) received an average dose of 0.42 × 106 cells/kg through intrathecal administration at the cervical, thoracic or lumbar region depending on the clinical symptoms. There was a 2 month interval between two injections. The adverse events occurring during a 6-month treatment period were evaluated. No adverse events occurred. Headache occurred in one case only after first injection of stem cells. This suggests that intrathecal injection of Wharton's Jelly-derived mesenchymal stem cells is well tolerated in patients with amyotrophic lateral sclerosis. This study was approved by the Bioethical Committee of School of Medicine, University of Warmia and Mazury in Olsztyn, Poland(approval No. 36/2014 and approval No. 8/2016). This study was registered with the ClinicalTrials.gov(identifier: NCT02881476)on August 29, 2016.

Promising application of a new ulnar nerve compound muscle action potential measurement montage in amyotrophic lateral sclerosis:a prospective cross-sectional study

Previous studies have shown that ulnar nerve compound muscle action potential recorded by the conventional“belly-tendon”montage does not accurately and completely reflect the action potential of the ulnar nerve dominating the abductor digiti minimi muscle due to the effects of far-field potentials of intrinsic hand muscles.A new method of ulnar nerve compound muscle action potential measurement was developed in 2020,which adjusts the E2 electrode from the distal tendon of the abductor digitorum to the middle of the back of the proximal wrist.This new method may reduce the influence of the reference electrode and better reflect the actual ulnar nerve compound muscle action potential.In this prospective cross-sectional study,we included 64 patients with amyotrophic lateral sclerosis and 64 age-and sex-matched controls who underwent conventional and novel ulnar nerve compound muscle action potential measurement between April 2020 and May 2021 in Peking University Third Hospital.The compound muscle action potential waveforms recorded by the new montage were unimodal and more uniform than those recorded by traditional montage.In the controls,no significant difference in the compound muscle action potential waveforms was found between the traditional montage and new montage recordings.In amyotrophic lateral sclerosis patients presenting with abductor digiti minimi spontaneous activity and muscular atrophy,the amplitude of compound muscle action potential-pE2 was significantly lower than that of compound muscle action potential-dE2(P<0.01).Using the new method,damaged axons were more likely to exhibit more severe amplitude decreases than those measured with the traditional method,in particular for patients in early stage amyotrophic lateral sclerosis.In addition,the decline in compound muscle action potential amplitude measured by the new method was correlated with a decrease in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale scores.These findings suggest that the new ulnar nerve compound muscle action potential measurement montage reduces the effects of the reference electrode through altering the E2 electrode position,and that this method is more suitable for monitoring disease progression than the traditional montage.This method may be useful as a biomarker for longitudinal follow-up and clinical trials in amyotrophic lateral sclerosis.

State of the art and the dark side of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis(ALS) is a disorder that involves the degeneration of motor neurons,muscle atrophy,and paralysis.In a few familiar forms of ALS,mutations in the superoxide dismutase-1(SOD1) gene have been held responsible for the degeneration of motor neurons.Nevertheless,after the discovery of the SOD1 mutations no consensus has emerged as to which cells,tissues and pathways are primarily implicated in the pathogenic events that lead to ALS.Ubiquitous overexpression of mutant SOD1 in transgenic animals recapitulates the pathological features of ALS.However,the toxicity of mutant SOD1 is not necessarily limited to the central nervous system.Views about ALS pathogenesis are now enriched by the recent discovery of mutations in a pair of DNA/RNA-binding proteins called TDP-43 and FUS/TLS as causes of familial and sporadic forms of ALS.Although the steps that lead to the pathological state are well defined,several fundamental issues are still controversial:are the motor neurons the first direct targets of ALS;and what is the contribution of non-neuronal cells,if any,to the pathogenesis of ALS?The state of the art of ALS pathogenesis and the open questions are discussed in this review.

Treating amyotrophic lateral sclerosis with allogeneic Schwann cell-derived exosomal vesicles: a case report

Schwann cells are essential for the maintenance and function of motor neurons,axonal networks,and the neuromuscular junction.In amyotrophic lateral sclerosis,where motor neuron function is progressively lost,Schwann cell function may also be impaired.Recently,important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported.This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles,marking,to our knowledge,the first instance of such treatment.An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis.After initial diagnosis,the patient underwent a combination of generic riluzole,sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis,and taurursodiol.The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function.We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired(senescent)and that exposure of the patient’s Schwann cells to allogeneic Schwann cell-derived exosomal vesicles,cultured expanded from a cadaver donor improved their growth capacity in vitro.After a period of observation lasting 10 weeks,during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored,the patient received weekly consecutive infusions of 1.54×1012(×2),and then consecutive infusions of 7.5×1012(×6)allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco’s phosphate-buffered saline.None of the infusions were associated with adverse events such as infusion reactions(allergic or otherwise)or changes in vital signs.Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend.A more sensitive in-house assay suggested possible inflammasome activation during the disease course.A trend for clinical stabilization was observed during the infusion period.Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles.Initial findings suggest that this approach is safe.

5-Hydroxytryptamine:a potential therapeutic target in amyotrophic lateral sclerosis

Previous studies have indicated that the pathogenesis of amyotrophic lateral sclerosis(ALS) is closely linked to 5-hydroxytryptamine(5-HT).To investigate this further,we administered 5-HT receptor antagonists to SOD1*G93A transgenic(ALS mouse model) and wide-type mice.This involved intraperitoneal injections of either granisetron,piboserod,or ritanserin,which inhibit the 5-HT3,5-HT4,and 5-HT2 receptors,respectively.The transgenic mice were found to have fewer5-HT-positive cells in the spinal cord compared with wide-type mice.We found that the administration of granisetron reduced the body weight of the transgenic mice,while piboserod and ritanserin worsened the motor functioning,as assessed using a hanging wire test.However,none of the 5-HT receptor antagonists affected the disease progression.We analyzed the distribution and/or expression of TAR DNA binding protein 43(TDP-43) and superoxide dismutase 1 G93A(SOD1-G93A),which fo rm abnormal aggregates in ALS.We found that the expression of these proteins increased following the administration of all three 5-HT receptor antagonists.In addition,the disease-related mislocalization of TD P-43 to the cytoplasm increased markedly for all three drugs.In ce rtain anatomical regions,the 5-HT receptor antagonists also led to a marked increase in the number of astrocytes and microglia and a decrease in the number of neurons.These results indicate that 5-HT deficiency may play a role in the pathogenesis of amyotrophic lateral sclerosis by inducing the abnormal expression and/or distribution of TDP-43 and SOD1-G93A and by activating glial cells.5-HT co uld therefore be a potential therapeutic target for amyotrophic lateral sclerosis.

Pathological mechanisms of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis refers to a neurodegenerative disease involving the motor system,the cause of which remains unexplained despite several years of research.Thus,the journey to understanding or treating amyotrophic lateral sclerosis is still a long one.According to current research,amyotrophic lateral sclerosis is likely not due to a single factor but rather to a combination of mechanisms mediated by complex interactions between molecular and genetic pathways.The progression of the disease involves multiple cellular processes and the interaction between different complex mechanisms makes it difficult to identify the causative factors of amyotrophic lateral sclerosis.Here,we review the most common amyotrophic lateral sclerosis-associated pathogenic genes and the pathways involved in amyotrophic lateral sclerosis,as well as summarize currently proposed potential mechanisms responsible for amyotrophic lateral sclerosis disease and their evidence for involvement in amyotrophic lateral sclerosis.In addition,we discuss current emerging strategies for the treatment of amyotrophic lateral sclerosis.Studying the emergence of these new therapies may help to further our understanding of the pathogenic mechanisms of the disease.

Gray Matter Volume Changes over the Whole Brain in the Bulbar-and Spinal-onset Amyotrophic Lateral Sclerosis: a Voxel-based Morphometry Study

Objective To investigate cerebral structural signatures of the bulbar-and spinal-onset amyotrophic lateral sclerosis(ALS) using voxel-based morphometry on magnetic resonance imaging.Methods The MR structural images of the brain were obtained from 65 ALS patients(15 bulbar-onset, 50 spinalonset) and 65 normal controls(NC) on a 3.0 T MRI system. Gray matter(GM) volume changes were investigated by voxel-based morphometry, and the distribution of the brain regions with volume changes was compared between ALS and normal controls, as well as between bulbar-onset and spinal-onset ALS based on Neuromorphometrics atlas.Results On voxel-level the decreased volume of brain regions in ALS patients was located in the right precentral gyrus(r Prc Gy) and right middle frontal gyrus compared with that in NC. The bulbar-onset ALS presented extramotor cortex atrophy(fronto-temporal pattern), including left medial orbital gyrus, left inferior temporal gyrus and right middle temporal gyrus; the spinal-onset ALS suffered from motor cortex atrophy(r Prc Gy dominance) and extra-motor cortex atrophy(fronto-temporal and extra-fronto-temporal pattern) compared with NC. The spinal-onset ALS featured by GM volume loss of left postcentral gyrus and bulbar-onset ALS featured by GM volume loss of left middle temporal gyrus compared with each other. Conclusions The asymmetric GM atrophy of the motor cortex and extra-motor cortex represents the common MRI structural signatures of spinal-onset ALS, and sole extra-motor cortex atrophy represents the structural signatures of bulbar-onset ALS. The present study also demonstrated that the pattern of GM damage is likely to distribute wider in spinal-onset ALS than in bulbar-onset ALS.

A candidate protective factor in amyotrophic lateral sclerosis:heterogenous nuclear ribonucleoprotein G

Heterogenous nuclear ribonucleoprotein G is down-regulated in the spinal cord of the Tg(SOD1*G93A)1Gur(TG)amyotrophic lateral sclerosis mouse model.However,most studies have only examined heterogenous nuclear ribonucleoprotein G expression in the amyotrophic lateral sclerosis model and heterogenous nuclear ribonucleoprotein G effects in amyotrophic lateral sclerosis pathogenesis such as in apoptosis are unknown.In this study,we studied the potential mechanism of heterogenous nuclear ribonucleoprotein G in neuronal death in the spinal cord of TG and wild-type mice and examined the mechanism by which heterogenous nuclear ribonucleoprotein G induces apoptosis.Heterogenous nuclear ribonucleoprotein G in spinal cord was analyzed using immunohistochemistry and western blotting,and cell proliferation and proteins(TAR DNA binding protein 43,superoxide dismutase 1,and Bax)were detected by the Cell Counting Kit-8 and western blot analysis in heterogenous nuclear ribonucleoprotein G siRNA-transfected PC12 cells.We analyzed heterogenous nuclear ribonucleoprotein G distribution in spinal cord in the amyotrophic lateral sclerosis model at various time points and the expressions of apoptosis and proliferation-related proteins.Heterogenous nuclear ribonucleoprotein G was mainly localized in neurons.Amyotrophic lateral sclerosis mice were examined at three stages:preonset(60-70 days),onset(90-100 days)and progression(120-130 days).The number of heterogenous nuclear ribonucleoprotein G-positive cells was significantly higher in the anterior horn of the lumbar spinal cord segment of TG mice at the preonset stage than that of control group but lower than that of the control group at the onset stage.The number of heterogenous nuclear ribonucleoprotein G-positive cells in both central canal and surrounding gray matter of the whole spinal cord of TG mice at the onset stage was significantly lower than that in the control group,whereas that of the lumbar spinal cord segment of TG mice was significantly higher than that in the control group at preonset stage and significantly lower than that in the control group at the progression stage.The numbers of heterogenous nuclear ribonucleoprotein G-positive cells in the posterior horn of cervical and thoracic segments of TG mice at preonset and progression stages were significantly lower than those in the control group.The expression of heterogenous nuclear ribonucleoprotein G in the cervical spinal cord segment of TG mice was significantly higher than that in the control group at the preonset stage but significantly lower at the progression stage.The expression of heterogenous nuclear ribonucleoprotein G in the thoracic spinal cord segment of TG mice was significantly increased at the preonset stage,significantly decreased at the onset stage,and significantly increased at the progression stage compared with the control group.heterogenous nuclear ribonucleoprotein G expression in the lumbar spinal cord segment of TG mice was significantly lower than that of the control group at the progression stage.After heterogenous nuclear ribonucleoprotein G gene silencing,PC12 cell survival was lower than that of control cells.Both TAR DNA binding protein 43 and Bax expressions were significantly increased in heterogenous nuclear ribonucleoprotein G-silenced cells compared with control cells.Our study suggests that abnormal distribution and expression of heterogenous nuclear ribonucleoprotein G might play a protective effect in amyotrophic lateral sclerosis development via preventing neuronal death by reducing abnormal TAR DNA binding protein 43 generation in the spinal cord.

Intention Formation Process for the Use of Tracheostomy and Invasive Ventilation in Patients with Amyotrophic Lateral Sclerosis

Background: Little is known about the intention formation process regarding the use of tracheostomy and invasive ventilation (TIV) in amyotrophic lateral sclerosis (ALS) patients in the course of disease progression. Objective: To clarify the intention formation process in the use of TIV in ALS patients for the purpose of providing decision-making support. Methods: We conducted a follow-up study of 14 patients using semi-structured interviews, participant observation, and medical records review. Results: The patients’ various intentions regarding the use of TIV were formed as their symptoms progressed (e.g., declining motor, swallowing, and respiratory functions). Other factors influencing their decision were their considerations, such as their ability to communicate after receiving TIV treatment, the degree of support they would receive from professionals after TIV treatment, palliative care for physical distress, value of life after TIV treatment, and to what degree they would be a burden on their families. Conclusion: Patients’ intentions regarding the use of TIV were diverse and changeable. The decision of whether or not to use TIV was made out of conviction as well as considering individual experiences of symptom progression and quality of life after TIV use.

Fungal-contaminated grass and well water and sporadic amyotrophic lateral sclerosis

Fungi are important infectious disease-causing agents,but are often overlooked as environmental factors in disease.We review several lines of evidence that point to a potential fungal origin of sporadic amyotrophic lateral sclerosis(ALS),the most common form of motor neurone disease.Approximately 90%cases of ALS are sporadic,and the aetiology of sporadic ALS is still unknown.We have previously postulated that grass or soil-associated fungal infections may be a leading cause of sporadic ALS.Herein we extend this proposal to water-associated fungi.A wide variety of fungi have been reported in drinking water including Acremonium,Alternaria,Aspergillus,Cladosporium,Fusarium,Penicillium and Trichoderma.Some of these are known to produce neurotoxic mycotoxins.Despite this,drinking water is not routinely monitored for fungal contamination.Fungal contamination could explain the close correlation between distribution of well water and cases of sporadic ALS in the United States.We propose several mechanisms by which an opportunistic fungal infection from environmental exposure(to water,soil or plants)can lead to long term neuronal degradation resulting in the hallmarks of ALS.If confirmed,the association between fungal infection and sporadic ALS could lead to novel treatment strategies for this progressive and fatal disease.

MicroRNA biomarkers in frontotemporal dementia and to distinguish from Alzheimer's disease and amyotrophic lateral sclerosis

Frontotemporal lobar degeneration describes a group of progressive brain disorders that primarily are associated with atrophy of the prefrontal and anterior temporal lobes.Frontotemporal lobar degeneration is considered to be equivalent to frontotemporal dementia.Frontotemporal dementia is characterized by progressive impairments in behavior,executive function,and language.There are two main clinical subtypes:behavioral-variant frontotemporal dementia and primary progressive aphasia.The early diagnosis of frontotemporal dementia is critical for developing management strategies and interventions for these patients.Without validated biomarkers,the clinical diagnosis depends on recognizing all the core or necessary neuropsychiatric features,but misdiagnosis often occurs due to overlap with a range of neurologic and psychiatric disorders.In the studies reviewed a very large number of microRNAs were found to be dysregulated but with limited overlap between individual studies.Measurement of specific miRNAs singly or in combination,or as miRNA pairs(as a ratio)in blood plasma,serum,or cerebrospinal fluid enabled frontotemporal dementia to be discriminated from healthy controls,Alzheimer’s disease,and amyotrophic lateral sclerosis.Furthermore,upregulation of miR-223-3p and downregulation of miR-15a-5p,which occurred both in blood serum and cerebrospinal fluid,distinguished behavioral-variant frontotemporal dementia from healthy controls.Downregulation of miR-132-3p in frontal and temporal cortical tissue distinguished frontotemporal lobar degeneration and frontotemporal dementia,respectively,from healthy controls.Possible strong miRNA biofluid biomarker contenders for behavioral-variant frontotemporal dementia are miR-223-3p,miR-15a-5p,miR-22-3p in blood serum and cerebrospinal fluid,and miR-124 in cerebrospinal fluid.No miRNAs were identified able to distinguish between behavioral-variant frontotemporal dementia and primary progressive aphasia subtypes.Further studies are warranted on investigating miRNA expression in biofluids and frontal/temporal cortical tissue to validate and extend these findings.

Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury

Neglected for years, astrocytes are now recognized to fulfill and support many, if not all, homeostatic functionsof the healthy central nervous system(CNS). During neurodegenerative diseases such as amyotrophic lateral sclerosis(ALS) and spinal cord injury(SCI), astrocytes in the vicinity of degenerating areas undergo both morphological and functional changes that might compromise their intrinsic properties. Evidence from human and animal studies show that deficient astrocyte functions or loss-of-astrocytes largely contribute to increased susceptibility to cell death for neurons, oligodendrocytes and axons during ALS and SCI disease progression. Despite exciting advances in experimental CNS repair, most of current approaches that are translated into clinical trials focus on the replacement or support of spinal neurons through stem cell transplantation, while none focus on the specific replacement of astroglial populations. Knowing the important functions carried out by astrocytes in the CNS, astrocyte replacement-based therapies might be a promising approach to alleviate overall astrocyte dysfunction, deliver neurotrophic support to degenerating spinal tissue and stimulate endogenous CNS repair abilities. Enclosed in this review, we gathered experimental evidence that argue in favor of astrocyte transplantation during ALS and SCI. Based on their intrinsic properties and according to the cell type transplanted, astrocyte precursors or stem cell-derived astrocytes promote axonal growth, support mechanisms and cells involved in myelination, are able to modulate the host immune response, deliver neurotrophic factors and provide protective molecules against oxidative or excitotoxic insults, amongst many possible benefits. Embryonic or adult stem cells can even be genetically engineered in order to deliver missing gene products and therefore maximize the chance of neuroprotection and functional recovery. However, before broad clinical translation, further preclinical data on safety, reliability and therapeutic efficiency should be collected. Although several technical challenges need to be overcome, we discuss the major hurdles that have already been met or solved by targeting the astrocyte populationin experimental ALS and SCI models and we discuss avenues for future directions based on latest molecular findings regarding astrocyte biology.