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Mutations in the superoxide dismutase 1 gene (SOD1) are associated with familial ALS but the role of SOD1 in sporadic ALS (SALS) is unclear. We therefore sequenced the entire SOD1 gene in 23 patients with SALS. DNA was extracted from frozen pre-frontal cerebral cortex and from blood. The 5 exons, 4 introns and 1 kb upstream and downstream of SOD1 were sequenced. Novel genetic variants were found in 30% (7 of 23) brains and known variants in 91% (21 of 23) brains from patients with SALS. Two novel variants found in SALS patients and not controls were located in the SOD1 promoter and intron 1, with the promoter variant having potential functional implications. A previously described silent variant in exon 5 in one SALS patient appears to abolish an exonic splicing enhancer. All changes found in brain DNA were also found in blood DNA. In conclusion, sequencing the entire SOD1 gene revealed 3 variants in SALS patients that were not detected in controls. Although no unequivocal mutations were found, some of these variants have potential consequences for SALS pathogenesis. 相似文献
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Scott WK Yamaoka LH Bass MP Gaskell PC Conneally PM Small GW Farrer LA Auerbach SA Saunders AM Roses AD Haines JL Pericak-Vance MA 《Neurogenetics》1998,1(3):179-183
The low-density lipoprotein receptor-related protein gene (LRP1) is often mentioned as a candidate gene for Alzheimer disease (AD) because of its role as a receptor for apolipoprotein E
(apoE), a major genetic risk factor for late-onset familial and sporadic AD. A recent association study of a tetranucleotide
repeat polymorphism located 5′ to the LRP1 gene detected an increase in the 87 base pair allele in AD cases compared to unaffected controls. Additionally, an independent
study involving a genomic screen for genes associated with late-onset AD identified a region as a possible location of a late-onset
AD gene on chromosome 12p between D12S373 and D12S390, about 10 cM proximal to LRP1. We examined 144 late-onset multiplex AD families, 436 sporadic AD cases, and 240 controls and found no evidence of linkage
or association of LRP1 and AD. Our data indicate that genetic variation of the LRP1 gene is not a major risk factor in the etiology of AD.
Received: June 16, 1997 / Accepted: August 10, 1997 相似文献
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Ascherio A 《Neurology》2005,65(6):972-3; author reply 972-3
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NLRP3 inflammasome is expressed by astrocytes in the SOD1 mouse model of ALS and in human sporadic ALS patients
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Sonja Johann Marius Heitzer Mithila Kanagaratnam Anand Goswami Tania Rizo Joachim Weis Dirk Troost Cordian Beyer 《Glia》2015,63(12):2260-2273
Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of motoneurons in the cerebral cortex, brainstem and spinal cord. Neuroinflammation plays an important role in the pathogenesis of ALS and involves the activation of microglia and astrocytes. Intracellular inflammasome complexes are part of the innate immunity as they sense and execute host inflammatory responses. The best characterized component is the NLRP3 inflammasome comprised of the NLR protein NLRP3, the adaptor ASC and pro‐caspase 1. The NLRP3 inflammasome is critical for the activation of caspase 1 and the processing and release of IL1β and IL18. In this study, we investigated the expression, activation and co‐localization of the NLRP3 inflammasome in the spinal cord of male SOD1(G93A) mice carrying a mutant human superoxide dismutase 1 (SOD1) variant and regarded as an animal model for ALS as well as in post‐mortem tissue of ALS patients. NLRP3 and its molecular components as well as IL1β were already detectable in SOD1 mice at a pre‐symptomatic stage after 9 weeks and further increased in 14 week old animals. Spinal cord astrocytes were identified as the major cell type expressing NLRP3 components. In human ALS tissue, we also found increased NLRP3, ASC, IL18 and active caspase 1 levels compared to control patients. Our findings suggest that astroglial NLRP3 inflammasome complexes are critically involved in neuroinflammation in ALS. GLIA 2015;63:2260–2273 相似文献
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Turner MR Osei-Lah AD Hammers A Al-Chalabi A Shaw CE Andersen PM Brooks DJ Leigh PN Mills KR 《Journal of neurology, neurosurgery, and psychiatry》2005,76(9):1279-1285
BACKGROUND: Excitotoxicity is one pathogenic mechanism proposed in amyotrophic lateral sclerosis (ALS), and loss of cortical inhibitory influence may be contributory. Patients with ALS who are homozygous for the D90A superoxide dismutase-1 (SOD1) gene mutation (homD90A) have a unique phenotype, associated with prolonged survival compared with patients with sporadic ALS (sALS). In this study, transcranial magnetic stimulation (TMS) was used to explore cortical excitation and inhibition. Flumazenil binds to the benzodiazepine subunit of the GABA(A) receptor, and (11)C-flumazenil positron emission tomography (PET) was used as a marker of cortical neuronal loss and/or dysfunction, which might in turn reflect changes in cortical inhibitory GABAergic mechanisms. METHODS: Cortical responses to single and paired stimulus TMS were compared in 28 patients with sALS and 11 homD90A patients versus 24 controls. TMS measures included resting motor threshold, central motor conduction time, silent period, intracortical inhibition (ICI), and facilitation. (11)C-flumazenil PET of the brain was performed on 20 patients with sALS and nine with homD90A. Statistical parametric mapping was used to directly compare PET images from the two patient groups to identify those areas of relatively reduced cortical (11)C-flumazenil binding that might explain differences in cortical excitability seen using TMS. RESULTS: Increased cortical excitability, demonstrated by reduction in ICI, was seen in the patients with sALS but not the homD90A patients. A relative reduction in cortical (11)C-flumazenil binding was found in the motor and motor association regions of the superior parietal cortices of the patients with sALS. CONCLUSIONS: A cortical inhibitory deficit in sALS was not demonstrable in a homogeneous genetic ALS population of similar disability, suggesting a distinct cortical vulnerability. (11)C-flumazenil PET demonstrated that neuronal loss/dysfunction in motor and motor association areas may underlie this difference. The corollary, that there may be relative preservation of neuronal function in these areas in the homD90A group, has implications for understanding the slower progression of disease in these patients. 相似文献
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Kato S Kato M Abe Y Matsumura T Nishino T Aoki M Itoyama Y Asayama K Awaya A Hirano A Ohama E 《Acta neuropathologica》2005,110(2):101-112
Peroxiredoxin-ll (Prxll) and glutathione peroxidase-l (GPxl) are regulators of the redox system that is one of the most crucial supporting systems in neurons. This system is an antioxidant enzyme defense system and is synchronously linked to other important cell supporting systems. To clarify the common self-survival mechanism of the residual motor neurons affected by amyotrophic lateral sclerosis (ALS), we examined motor neurons from 40 patients with sporadic ALS (SALS) and 5 patients with superoxide dismutase 1 (SOD1)-mutated familial ALS (FALS) from two different families (frame-shift 126 mutation and A4 V) as well as four different strains of the SOD1-mutated ALS models (H46R/G93A rats and G1H/G1L-G93A mice). We investigated the immunohistochemical expression of Prxll/GPxl in motor neurons from the viewpoint of the redox system. In normal subjects, Prxll/GPxl immunoreactivity in the anterior horns of the normal spinal cords of humans, rats and mice was primarily identified in the neurons: cytoplasmic staining was observed in almost all of the motor neurons. Histologically, the number of spinal motor neurons in ALS decreased with disease progression. Immunohistochemically, the number of neurons negative for Prxll/GPxl increased with ALS disease progression. Some residual motor neurons coexpressing Prxll/GPxl were, however, observed throughout the clinical courses in some cases of SALS patients, SOD1-mutated FALS patients, and ALS animal models. In particular, motor neurons overexpressing Prxll/GPxl, i.e., neurons showing redox system up-regulation, were commonly evident during the clinical courses in ALS. For patients with SALS, motor neurons overexpressing Prxll/GPxl were present mainly within approximately 3 years after disease onset, and these overexpressing neurons thereafter decreased in number dramatically as the disease progressed. For SOD1-mutated FALS patients, like in SALS patients, certain residual motor neurons without inclusions also overexpressed Prxll/GPxl in the short-term-surviving FALS patients. In the ALS animal models, as in the human diseases, certain residual motor neurons showed overexpression of Prxll/GPxl during their clinical courses. At the terminal stage of ALS, however, a disruption of this common Prxll/GPxl-overexpression mechanism in neurons was observed. These findings lead us to the conclusion that the residual ALS neurons showing redox system up-regulation would be less susceptible to ALS stress and protect themselves from ALS neuronal death, whereas the breakdown of this redox system at the advanced disease stage accelerates neuronal degeneration and/or the process of neuronal death. 相似文献
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SOD1 transgenic mice are the most widely used animal model of amyotrophic lateral sclerosis (ALS). In addition to providing valuable insights into the pathogenesis of ALS, these animals are used intensively in many laboratories as an in vivo model for investigating novel therapeutic interventions towards this devastating motorneuron disease. Such pre-clinical studies require objective and reliable quantification of the clinical phenotype of individual mice, most importantly of the neuromuscular abnormalities. Here we compare four parameters of the clinical phenotype: motor signs, body weight, rotarod performance and paw grip endurance for their usefulness in monitoring the SOD1 mouse model. We found that paw grip endurance is a sensitive and inexpensive alternative to the widely used rotarod test. 相似文献
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XIAO Y. DAI MINEKO HATTORI JUN YOSHIZAWA HIROSHI MATSUDA HEII ARAI SEIICHI AKIZUKI SHINICHIRO NANKO 《Psychiatry and clinical neurosciences》1996,50(6):331-333
Abstract Although ApoE ε4 is a major risk factor for sporadic Alzheimer's disease (AD), 20–30% of sporadic AD patients do not have this allele. This indicates that other risk factors are involved in the pathogenesis of sporadic AD. Studies of the genetic association between AD and polymorphisms in the c-fos gene, a candidate gene for AD, were conducted. The polymorphisms of Dsal in exon 2 and Sau3Al in intron 2 were examined in 89 patients diagnosed as sporadic cases of probable AD clinically and radiologically according to the NINCDS-ADRDA criteria. This was also undertaken in 96 controls. There was no significant difference between the groups in allele frequencies or genotype counts. Although c-fos gene as a locus conferring susceptibility to sporadic AD cannot be ruled out, these data could not support the hypothesis that a c-fos allele should be another risk factor for sporadic AD. 相似文献
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No association between presenilin 1 (PS1) intronic polymorphism and sporadic Alzheimer's disease in Koreans 总被引:1,自引:0,他引:1
Kim KW Jhoo JH Lee KU Lee DY Lee JH Youn JY Lee BJ Woo JI 《Journal of neural transmission (Vienna, Austria : 1996)》2000,107(10):1191-1120
Summary. To investigate the possible involvement of an intronic polymorphism in the presenilin 1 (PS1) gene and its interactions with
the aplolipoprotein E (APOE) or alpha-1 antichymotrypsin (ACT) polymorphisms in the manifestation of AD, we analyzed the PS1,
APOE and ACT genotypes of 100 sporadic AD patients and 199 normal elderly controls in Koreans. The genotypic (χ2 = 0.92, df = 2, P > 0.1) and allelic (χ2 = 0.01, df = 1, P > 0.1) frequencies of the PS1 polymorphism in the late- and early-onset sporadic AD patients did not differ
from those in the controls. And the occurrence of the APOE ε4 allele and ACT A allele did not influence the distribution of
the PS1 intronic polymorphism. The PS1 intronic polymorphism didn't influence the age-at-onset of AD (F = 0.02, df = 2, P
> 0.1). In conclusion, the PS1 intronic polymorphism did not modify the risk for sporadic AD, neither independently nor synergistically
with the APOE ε4 allele or ACT A allele, in Koreans.
Received December 24, 1999; accepted March 18, 2000 相似文献
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Chen W Saeed M Mao H Siddique N Dellefave L Hung WY Deng HX Sufit RL Heller SL Haines JL Pericak-Vance M Siddique T 《Neurology》2006,67(3):508-510
The authors tested the association of three vascular endothelial growth factor (VEGF) promoter polymorphisms with sporadic ALS (SALS) to verify the results of a previous study and to investigate their modifier effects on the subphenotypes of SALS in a large family-based and case-control cohort of North American white subjects (N = 1,603). They did not find any association of the VEGF promoter polymorphisms with SALS or its subphenotypes, suggesting that they do not have a direct causal role in ALS. 相似文献
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Sato T Nakanishi T Yamamoto Y Andersen PM Ogawa Y Fukada K Zhou Z Aoike F Sugai F Nagano S Hirata S Ogawa M Nakano R Ohi T Kato T Nakagawa M Hamasaki T Shimizu A Sakoda S 《Neurology》2005,65(12):1954-1957
Studies on the clinical course of familial ALS suggest that the duration of illness is relatively consistent for each mutation but variable among the different mutations. The authors analyzed the relative amount of mutant compared with normal SOD1 protein in the erythrocytes from 29 patients with ALS with 22 different mutations. Turnover of mutant SOD1 correlated with a shorter disease survival time. 相似文献
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Familial amyotrophic lateral sclerosis (ALS) is frequently associated with mutations in the SOD1 gene. We identified a rapidly progressive disease in a patient with an inherited ALS. The identified heterozygous T>A exchange in position 1067 in the SOD1 gene results in an amino acid substitution of lysine for asparagine at position 86 (N86K) of the SOD1 protein. The family history suggested that this autosomal dominantly inherited mutation may be associated with rapidly progressive disease. 相似文献
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Ohkubo T Shibata N Ohnuma T Higashi S Usui C Ueki A Nagao M Arai H 《Dementia and geriatric cognitive disorders》2005,20(2-3):95-98
The identification of the epsilon4 variant of apolipoprotein E as a genetic risk factor for late-onset Alzheimer's disease (AD) suggests that cholesterol may play a direct role in the pathogenesis of the disease. Recent studies have suggested that the ATP-binding cassette (ABC) protein G5 (ABCG5) may be involved in the regulation of intestinal cholesterol absorption. Furthermore, genetic variation of this locus may affect blood cholesterol concentrations. We therefore studied whether the ABCG5 C1950G (Gln640Glu) polymorphism affects the risk of AD. In addition, there was no difference in mean baseline cholesterol concentrations between individuals with the C/C genotype and carriers of the G allele. Recent studies have shown that genetic regions including the ABCA12 gene might also be associated with the risk of AD. The ABCA12 gene, located <1 Mb from the peak marker on chromosome 2q34, is also a member of the ABC transporter superfamily. In the current study, two common polymorphisms of the ABCA12 gene, rs952718 (T/G) and rs956133 (A/G), were analyzed in our subjects. These polymorphisms showed no association with the risk of AD. Furthermore, we observed weak linkage disequilibrium between these two single nucleotide polymorphisms. These results indicate that the common polymorphisms of the ABCG5 and ABCA12 genes investigated here are not associated with AD. 相似文献