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
Among neurodegenerative diseases,amyotrophic lateral sclerosis(ALS)is the most frequent one involving motor neurons(MNs).ALS incidence varies throughout the world ranging from 0.7 to 4 cases per 100,000 habitants and ...Among neurodegenerative diseases,amyotrophic lateral sclerosis(ALS)is the most frequent one involving motor neurons(MNs).ALS incidence varies throughout the world ranging from 0.7 to 4 cases per 100,000 habitants and year(Riancho et al.,2016).This disease,which currently lacks an effective therapy,is characterized by a variable combination of upper and lower MN degeneration,leading to progressive muscle wasting which usually results in a terminal respiratory failure within 3 years after symptom onset(Zufiria et al.,2016).A small proportion of ALS cases show familial aggregation.These are related to mutations in specific causative genes(Cr9ORF72,TARDBP,FUS,SOD1 and others)which directly determine disease onset in carriers.By contrast,more than 90 percent of cases are considered to be sporadic,in which generally unknown environmental and internal factors interact with genetic predisposing factors finally leading to disease(Riancho et al.,2018).From a histopathological point of view,ALS is characterized by MN damage and loss.MNs from ALS sporadic and most of familial patients exhibit prominent transactive response DNA-binding protein 43(TDP-43)cytoplasmic aggregates which are considered as the“pathological hallmark”of the disease,excepting those related to SOD1 and FUS mutations(Zufiria et al.,2016).TDP-43 is a DNA/RNA binding protein encoded by the TARDBP gene that controls the expression of many different genes.展开更多
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Among neurodegenerative diseases,amyotrophic lateral sclerosis(ALS)is the most frequent one involving motor neurons(MNs).ALS incidence varies throughout the world ranging from 0.7 to 4 cases per 100,000 habitants and year(Riancho et al.,2016).This disease,which currently lacks an effective therapy,is characterized by a variable combination of upper and lower MN degeneration,leading to progressive muscle wasting which usually results in a terminal respiratory failure within 3 years after symptom onset(Zufiria et al.,2016).A small proportion of ALS cases show familial aggregation.These are related to mutations in specific causative genes(Cr9ORF72,TARDBP,FUS,SOD1 and others)which directly determine disease onset in carriers.By contrast,more than 90 percent of cases are considered to be sporadic,in which generally unknown environmental and internal factors interact with genetic predisposing factors finally leading to disease(Riancho et al.,2018).From a histopathological point of view,ALS is characterized by MN damage and loss.MNs from ALS sporadic and most of familial patients exhibit prominent transactive response DNA-binding protein 43(TDP-43)cytoplasmic aggregates which are considered as the“pathological hallmark”of the disease,excepting those related to SOD1 and FUS mutations(Zufiria et al.,2016).TDP-43 is a DNA/RNA binding protein encoded by the TARDBP gene that controls the expression of many different genes.
