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 ...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.展开更多
Amyotrophic lateral sclerosis, the most common neurodegenerative disease affecting motor neurons, lacks an effective treatment. A small fraction of amyotrophic lateral sclerosis cases have a familial origin, related t...Amyotrophic lateral sclerosis, the most common neurodegenerative disease affecting motor neurons, lacks an effective treatment. A small fraction of amyotrophic lateral sclerosis cases have a familial origin, related to mutations in causative genes, while the vast majority of amyotrophic lateral sclerosis cases are considered to be sporadic, resulting from the interaction between genes and environmental factors in predisposed individuals. During the past few years, dozens of drugs have been postulated as promising strategies for the disease after showing some beneficial effects in preclinical cellular and murine models. However, the translation into clinical practice has been largely unsuccessful and the compounds failed when were tested in clinical trials. This might be explained, at least partially, by the enormous complexity of the disease both from clinico-epidemiological and a pathogenic points of view. In this review, we will briefly comment on the complexity of the disease focusing on some recent findings, and we will suggest how amyotrophic lateral sclerosis research might be reoriented to foster the advance in the diagnostic and therapeutic questions.展开更多
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 la...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.展开更多
The G93A-SOD1 mice model and MRI diffusion as a preclinical tool to study amyotrophic lateral sclerosis （ALS）： ALS is a progressive neurological disease characterized primarily by the development of limb paralysis,...The G93A-SOD1 mice model and MRI diffusion as a preclinical tool to study amyotrophic lateral sclerosis （ALS）： ALS is a progressive neurological disease characterized primarily by the development of limb paralysis, which eventually leads to lack of control on muscles under voluntary control and death within 3–5 years. Genetic heterogeneity and environmental factors play a critical role in the rate of disease progression and patients display faster declines once the symptoms have manifested. Since its original discovery, ALS has been associated with pathological alterations in motor neurons located in the spinal cord （SC）, where neuronal loss by a mutation in the protein superoxide dismutase in parenthesis （mSOD1） and impairment in axonal connectivity, have been linked to early functional impairments. In addition,mechanisms of neuroinflammation, apoptosis, necroptosis and autophagy have been also implicated in the development of this disease. Among different animal models developed to study ALS, the transgenic G93A-SOD1 mouse has become recognized as a benchmark model for preclinical screening of ALS therapies. Furthermore, the progressive alterations in the locomotor phenotype expressed in this model closely resemble the progressive lower limb dysfunction of ALS patients. Among other imaging tools, MR diffusion tensor imaging （DTI） has emerged as a crucial, noninvasive and real time neuroimaging tool to gather information in ALS. One of the current concerns with the use of DTI is the lack of biological validation of the microstructural information given by this technique. Although clinical studies using DTI can provide a remarkable insight on the targets of neurodegeneration and disease course,they lack histological correlations. To address these shortcomings, preclinical models can be designed to validate the microstructural information unveiled by this particular MRI technique. Thus, the scope of this review is to describe how MRI diffusion and optical microscopy evaluate axonal structural changes at early stages of the disease in a preclinical model of ALS.展开更多
Amyotrophic lateral sclerosis（ALS）is a progressively fatal neuromuscular disorder classically characterized by loss of upper and lower motor neurons from the cortex to the spinal cord Diagnosed patients have a media...Amyotrophic lateral sclerosis（ALS）is a progressively fatal neuromuscular disorder classically characterized by loss of upper and lower motor neurons from the cortex to the spinal cord Diagnosed patients have a median survival of about 3 years and death usually results from eventual respiratory failure.展开更多
Amyotrophic lateral sclerosis（ALS） is the most common degenerative disease of the motor neuron system. Over the last years, a growing interest was aimed to discovery new innovative and safer therapeutic approaches i...Amyotrophic lateral sclerosis（ALS） is the most common degenerative disease of the motor neuron system. Over the last years, a growing interest was aimed to discovery new innovative and safer therapeutic approaches in the ALS treatment. In this context, the bioactive compounds of Cannabis sativa have shown antioxidant, anti-inflammatory and neuroprotective effects in preclinical models of central nervous system disease. However, most of the studies proving the ability of cannabinoids in delay disease progression and prolong survival in ALS were performed in animal model, whereas the few clinical trials that investigated cannabinoids-based medicines were focused only on the alleviation of ALS-related symptoms, not on the control of disease progression. The aim of this report was to provide a short but important overview of evidences that are useful to better characterize the efficacy as well as the molecular pathways modulated by cannabinoids.展开更多
The hexanucleotide repeat mutation in the intron-1 of the chromosome 9 open reading frame (C9orf72) is a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Altered RNA folding pla...The hexanucleotide repeat mutation in the intron-1 of the chromosome 9 open reading frame (C9orf72) is a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Altered RNA folding plays a role in ALS pathogenesis in two ways: non-ATG translation of the repeat can lead to aggregates of the known C9orf72 specific dipeptide polymer, whereas the repeat also can form neurotoxic RNA inclusions that dose-responsively kill motor neurons. We report the presence of a homology in the 5’untranslated region (UTR) of the messenger RNA encoding C9orf72 with the iron responsive elements (IRE) that control expression of iron-associated transcripts and predict that this RNA structure may iron-dependently regulate C9orf72 translation. We previously report altered serum ferritin levels track with severity of ALS in patients. Here, we conduct bioinformatics analyses to determine the secondary structure of the 5’UTR in C9orf72 mRNA and find it aligned with IREs in the human mitochondrial cis-aconitase and L and H-ferritin transcripts. Comparison of the role of RNA repeats in Friedriech’s ataxia and fragile X mental retardation suggests the utility of RNA based therapies for treatment of ALS. Antisense oligonucleotides (ASO) have been reported to therapeutically target these GGGGCC repeats. At the same time, because the function of C9orf72 is unknown, knockdown strategies carry some risk of inducing or compounding haploinsufficiency. We propose, for consideration, an approach that may enhance its therapeutic dynamic range by increasing the 5’UTR driven translation of C9orf72 protein to compensate for any potential ALS-specific or ASO-induced haploinsufficieny.展开更多
Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understan...Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.展开更多
INTRODUCTION Amyotrophic lateral sclerosis （ALS） is a progressive neurodegenerative disease characterized by selective death of upper motor neurons （UMNs） and lower motor neurons （LMNs）, typically may die from r...INTRODUCTION Amyotrophic lateral sclerosis （ALS） is a progressive neurodegenerative disease characterized by selective death of upper motor neurons （UMNs） and lower motor neurons （LMNs）, typically may die from respiratory failure within 2-5 years of symptorn onset）H About 10% orALS patients are familial whereas the remaining patients are sporadic. ALS is highly heterogeneous in genetic and clinical phenotype, with lack of definitive diagnostic tools, making it extremely difficult to make early diagnosis.展开更多
Amyotrophic lateral sclerosis(ALS)is the most common adult-onset motor neuron disease.It is characterized by neuronal loss and degeneration of the upper motor neurons(UMNs)and lower motor neurons(LMNs),and is usually ...Amyotrophic lateral sclerosis(ALS)is the most common adult-onset motor neuron disease.It is characterized by neuronal loss and degeneration of the upper motor neurons(UMNs)and lower motor neurons(LMNs),and is usually fatal due to respiratory failure within 3–5 years of onset.Although approximately 5–10%of patients with ALS have an inherited form of the disease,the distinction between hereditary and apparently sporadic ALS(SALS)seems to be artificial.Thus,genetic factors play a role in all types of ALS,to a greater or lesser extent.During the decade of upheaval,the evolution of molecular genetics technology has rapidly advanced our genetic knowledge about the causes of ALS,and the relationship between the genetic subtypes and clinical phenotype.In this review,we will focus on the possible genotype-phenotype correlation in hereditary ALS.Uncovering the identity of the genetic factors in ALS will not only improve the accuracy of ALS diagnosis,but may also provide new approaches for preventing and treating the disease.展开更多
Amyotrophic lateral sclerosis(ALS)is a devastating neurodegenerative disease characterized by progressive neuronal loss and degeneration of upper motor neuron(UMN)and lower motor neuron(LMN).The clinical presentations...Amyotrophic lateral sclerosis(ALS)is a devastating neurodegenerative disease characterized by progressive neuronal loss and degeneration of upper motor neuron(UMN)and lower motor neuron(LMN).The clinical presentations of ALS are heterogeneous and there is no single test or procedure to establish the diagnosis of ALS.Most cases are diagnosed based on symptoms,physical signs,progression,EMG,and tests to exclude the overlapping conditions.Familial ALS represents about 5~10% of ALS cases,whereas the vast majority of patients are sporadic.To date,more than 20 causative genes have been identified in hereditary ALS.Detecting the pathogenic mutations or risk variants for each ALS individual is challenging.However,ALS patients carrying some specific mutations or variant may exhibit subtly distinct clinical features.Unraveling the respective genotype-phenotype correlation has important implications for the genetic explanations.In this review,we will delineate the clinical features of ALS,outline the major ALS-related genes,and summarize the possible genotype-phenotype correlations of ALS.展开更多
Amyotrophic lateral sclerosis(ALS)is a fatal disease characterized by the premature loss of motor neurons.While the underlying cellular mechanisms of neuron degeneration are unknown,the cytoplasmic aggregation of seve...Amyotrophic lateral sclerosis(ALS)is a fatal disease characterized by the premature loss of motor neurons.While the underlying cellular mechanisms of neuron degeneration are unknown,the cytoplasmic aggregation of several proteins is associated with sporadic and familial forms of the disease.Both wild-type and mutant forms of the RNA-binding proteins FUS and TDP-43 accumulate in cytoplasmic inclusions in the neurons of ALS patients.It is not known if these so-called proteinopathies are due to a loss of function or a gain of toxicity resulting from the formation of cytoplasmic aggregates.Here we present a model of FUS toxicity using the yeast Saccharomyces cerevisiae in which toxicity is associated with greater expression and accumulation of FUS in cytoplasmic aggregates.We find that FUS and TDP-43 have a high propensity for co-aggregation,unlike the aggregation patterns of several other aggregation-prone proteins.Moreover,the biophysical properties of FUS aggregates in yeast are distinctly different from many amyloidogenic proteins,suggesting they are not composed of amyloid.展开更多
Amyotrophic lateral sclerosis (ALS) also known as Lou Gehrig’s disease is a relentlessly progressive, fatal disease. Progression of the disease results 3 - 5 years after diagnosis, often from respiratory failure. The...Amyotrophic lateral sclerosis (ALS) also known as Lou Gehrig’s disease is a relentlessly progressive, fatal disease. Progression of the disease results 3 - 5 years after diagnosis, often from respiratory failure. The diaphragm pacing system (DPS) is a device that stimulates the diaphragm to maximally contract so patients can breathe more effectively. It has been used in patients with neurologic injuries such as spinal cord injury and ALS. From an anesthetic perspective, both the surgery and the patient population present several unique challenges. This case series describes three patients with ALS who had the diaphragmatic pacemaker placed and the anesthetic management during those surgeries.展开更多
文摘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.
文摘Amyotrophic lateral sclerosis, the most common neurodegenerative disease affecting motor neurons, lacks an effective treatment. A small fraction of amyotrophic lateral sclerosis cases have a familial origin, related to mutations in causative genes, while the vast majority of amyotrophic lateral sclerosis cases are considered to be sporadic, resulting from the interaction between genes and environmental factors in predisposed individuals. During the past few years, dozens of drugs have been postulated as promising strategies for the disease after showing some beneficial effects in preclinical cellular and murine models. However, the translation into clinical practice has been largely unsuccessful and the compounds failed when were tested in clinical trials. This might be explained, at least partially, by the enormous complexity of the disease both from clinico-epidemiological and a pathogenic points of view. In this review, we will briefly comment on the complexity of the disease focusing on some recent findings, and we will suggest how amyotrophic lateral sclerosis research might be reoriented to foster the advance in the diagnostic and therapeutic questions.
文摘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.
基金provided by the Chicago Biomedical Consortium’s Postdoctoral Research Award,No.085740
文摘The G93A-SOD1 mice model and MRI diffusion as a preclinical tool to study amyotrophic lateral sclerosis （ALS）： ALS is a progressive neurological disease characterized primarily by the development of limb paralysis, which eventually leads to lack of control on muscles under voluntary control and death within 3–5 years. Genetic heterogeneity and environmental factors play a critical role in the rate of disease progression and patients display faster declines once the symptoms have manifested. Since its original discovery, ALS has been associated with pathological alterations in motor neurons located in the spinal cord （SC）, where neuronal loss by a mutation in the protein superoxide dismutase in parenthesis （mSOD1） and impairment in axonal connectivity, have been linked to early functional impairments. In addition,mechanisms of neuroinflammation, apoptosis, necroptosis and autophagy have been also implicated in the development of this disease. Among different animal models developed to study ALS, the transgenic G93A-SOD1 mouse has become recognized as a benchmark model for preclinical screening of ALS therapies. Furthermore, the progressive alterations in the locomotor phenotype expressed in this model closely resemble the progressive lower limb dysfunction of ALS patients. Among other imaging tools, MR diffusion tensor imaging （DTI） has emerged as a crucial, noninvasive and real time neuroimaging tool to gather information in ALS. One of the current concerns with the use of DTI is the lack of biological validation of the microstructural information given by this technique. Although clinical studies using DTI can provide a remarkable insight on the targets of neurodegeneration and disease course,they lack histological correlations. To address these shortcomings, preclinical models can be designed to validate the microstructural information unveiled by this particular MRI technique. Thus, the scope of this review is to describe how MRI diffusion and optical microscopy evaluate axonal structural changes at early stages of the disease in a preclinical model of ALS.
基金supported by the NUS Graduate School for Integrative Sciences and Engineering
文摘Amyotrophic lateral sclerosis（ALS）is a progressively fatal neuromuscular disorder classically characterized by loss of upper and lower motor neurons from the cortex to the spinal cord Diagnosed patients have a median survival of about 3 years and death usually results from eventual respiratory failure.
文摘Amyotrophic lateral sclerosis（ALS） is the most common degenerative disease of the motor neuron system. Over the last years, a growing interest was aimed to discovery new innovative and safer therapeutic approaches in the ALS treatment. In this context, the bioactive compounds of Cannabis sativa have shown antioxidant, anti-inflammatory and neuroprotective effects in preclinical models of central nervous system disease. However, most of the studies proving the ability of cannabinoids in delay disease progression and prolong survival in ALS were performed in animal model, whereas the few clinical trials that investigated cannabinoids-based medicines were focused only on the alleviation of ALS-related symptoms, not on the control of disease progression. The aim of this report was to provide a short but important overview of evidences that are useful to better characterize the efficacy as well as the molecular pathways modulated by cannabinoids.
文摘The hexanucleotide repeat mutation in the intron-1 of the chromosome 9 open reading frame (C9orf72) is a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Altered RNA folding plays a role in ALS pathogenesis in two ways: non-ATG translation of the repeat can lead to aggregates of the known C9orf72 specific dipeptide polymer, whereas the repeat also can form neurotoxic RNA inclusions that dose-responsively kill motor neurons. We report the presence of a homology in the 5’untranslated region (UTR) of the messenger RNA encoding C9orf72 with the iron responsive elements (IRE) that control expression of iron-associated transcripts and predict that this RNA structure may iron-dependently regulate C9orf72 translation. We previously report altered serum ferritin levels track with severity of ALS in patients. Here, we conduct bioinformatics analyses to determine the secondary structure of the 5’UTR in C9orf72 mRNA and find it aligned with IREs in the human mitochondrial cis-aconitase and L and H-ferritin transcripts. Comparison of the role of RNA repeats in Friedriech’s ataxia and fragile X mental retardation suggests the utility of RNA based therapies for treatment of ALS. Antisense oligonucleotides (ASO) have been reported to therapeutically target these GGGGCC repeats. At the same time, because the function of C9orf72 is unknown, knockdown strategies carry some risk of inducing or compounding haploinsufficiency. We propose, for consideration, an approach that may enhance its therapeutic dynamic range by increasing the 5’UTR driven translation of C9orf72 protein to compensate for any potential ALS-specific or ASO-induced haploinsufficieny.
基金funded by NIH-NIA R01AG061708 (to PHO)Patrick Grange Memorial Foundation (to PHO)+1 种基金A Long Swim (to PHO)CureSPG4 Foundation (to PHO)。
文摘Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.
文摘INTRODUCTION Amyotrophic lateral sclerosis （ALS） is a progressive neurodegenerative disease characterized by selective death of upper motor neurons （UMNs） and lower motor neurons （LMNs）, typically may die from respiratory failure within 2-5 years of symptorn onset）H About 10% orALS patients are familial whereas the remaining patients are sporadic. ALS is highly heterogeneous in genetic and clinical phenotype, with lack of definitive diagnostic tools, making it extremely difficult to make early diagnosis.
基金by Grants-in-Aid for Science Research from the Ministry of Education,Culture,Sports,Science and Technology of Japan(No.24591269).
文摘Amyotrophic lateral sclerosis(ALS)is the most common adult-onset motor neuron disease.It is characterized by neuronal loss and degeneration of the upper motor neurons(UMNs)and lower motor neurons(LMNs),and is usually fatal due to respiratory failure within 3–5 years of onset.Although approximately 5–10%of patients with ALS have an inherited form of the disease,the distinction between hereditary and apparently sporadic ALS(SALS)seems to be artificial.Thus,genetic factors play a role in all types of ALS,to a greater or lesser extent.During the decade of upheaval,the evolution of molecular genetics technology has rapidly advanced our genetic knowledge about the causes of ALS,and the relationship between the genetic subtypes and clinical phenotype.In this review,we will focus on the possible genotype-phenotype correlation in hereditary ALS.Uncovering the identity of the genetic factors in ALS will not only improve the accuracy of ALS diagnosis,but may also provide new approaches for preventing and treating the disease.
基金This work was supported by grants from the National Natural Science Foundation to Zhi-Ying Wu(81125009,Beijing).
文摘Amyotrophic lateral sclerosis(ALS)is a devastating neurodegenerative disease characterized by progressive neuronal loss and degeneration of upper motor neuron(UMN)and lower motor neuron(LMN).The clinical presentations of ALS are heterogeneous and there is no single test or procedure to establish the diagnosis of ALS.Most cases are diagnosed based on symptoms,physical signs,progression,EMG,and tests to exclude the overlapping conditions.Familial ALS represents about 5~10% of ALS cases,whereas the vast majority of patients are sporadic.To date,more than 20 causative genes have been identified in hereditary ALS.Detecting the pathogenic mutations or risk variants for each ALS individual is challenging.However,ALS patients carrying some specific mutations or variant may exhibit subtly distinct clinical features.Unraveling the respective genotype-phenotype correlation has important implications for the genetic explanations.In this review,we will delineate the clinical features of ALS,outline the major ALS-related genes,and summarize the possible genotype-phenotype correlations of ALS.
基金This research was supported by Uniformed Services University of the Health Sciences and the Intramural Research Program of the National Institutes of Health,National Institute of Diabetes and Digestive and Kidney Diseases.
文摘Amyotrophic lateral sclerosis(ALS)is a fatal disease characterized by the premature loss of motor neurons.While the underlying cellular mechanisms of neuron degeneration are unknown,the cytoplasmic aggregation of several proteins is associated with sporadic and familial forms of the disease.Both wild-type and mutant forms of the RNA-binding proteins FUS and TDP-43 accumulate in cytoplasmic inclusions in the neurons of ALS patients.It is not known if these so-called proteinopathies are due to a loss of function or a gain of toxicity resulting from the formation of cytoplasmic aggregates.Here we present a model of FUS toxicity using the yeast Saccharomyces cerevisiae in which toxicity is associated with greater expression and accumulation of FUS in cytoplasmic aggregates.We find that FUS and TDP-43 have a high propensity for co-aggregation,unlike the aggregation patterns of several other aggregation-prone proteins.Moreover,the biophysical properties of FUS aggregates in yeast are distinctly different from many amyloidogenic proteins,suggesting they are not composed of amyloid.
文摘Amyotrophic lateral sclerosis (ALS) also known as Lou Gehrig’s disease is a relentlessly progressive, fatal disease. Progression of the disease results 3 - 5 years after diagnosis, often from respiratory failure. The diaphragm pacing system (DPS) is a device that stimulates the diaphragm to maximally contract so patients can breathe more effectively. It has been used in patients with neurologic injuries such as spinal cord injury and ALS. From an anesthetic perspective, both the surgery and the patient population present several unique challenges. This case series describes three patients with ALS who had the diaphragmatic pacemaker placed and the anesthetic management during those surgeries.
