scholarly journals Genetic Analysis of Tryptophan Metabolism Genes in Sporadic Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jennifer A. Fifita ◽  
Sandrine Chan Moi Fat ◽  
Emily P. McCann ◽  
Kelly L. Williams ◽  
Natalie A. Twine ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Synthesis ◽  
Genetic Basis ◽  
Late Onset ◽  
Whole Genome Sequencing Data ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Sequencing Data ◽  
Serotonin Synthesis ◽  
Sporadic Als ◽  
Lateral Sclerosis

The essential amino acid tryptophan (TRP) is the initiating metabolite of the kynurenine pathway (KP), which can be upregulated by inflammatory conditions in cells. Neuroinflammation-triggered activation of the KP and excessive production of the KP metabolite quinolinic acid are common features of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In addition to its role in the KP, genes involved in TRP metabolism, including its incorporation into proteins, and synthesis of the neurotransmitter serotonin, have also been genetically and functionally linked to these diseases. ALS is a late onset neurodegenerative disease that is classified as familial or sporadic, depending on the presence or absence of a family history of the disease. Heritability estimates support a genetic basis for all ALS, including the sporadic form of the disease. However, the genetic basis of sporadic ALS (SALS) is complex, with the presence of multiple gene variants acting to increase disease susceptibility and is further complicated by interaction with potential environmental factors. We aimed to determine the genetic contribution of 18 genes involved in TRP metabolism, including protein synthesis, serotonin synthesis and the KP, by interrogating whole-genome sequencing data from 614 Australian sporadic ALS cases. Five genes in the KP (AFMID, CCBL1, GOT2, KYNU, HAAO) were found to have either novel protein-altering variants, and/or a burden of rare protein-altering variants in SALS cases compared to controls. Four genes involved in TRP metabolism for protein synthesis (WARS) and serotonin synthesis (TPH1, TPH2, MAOA) were also found to carry novel variants and/or gene burden. These variants may represent ALS risk factors that act to alter the KP and lead to neuroinflammation. These findings provide further evidence for the role of TRP metabolism, the KP and neuroinflammation in ALS disease pathobiology.

scholarly journals Glutathione S-transferase Omega 2 DD genotype is associated with an increased risk of sporadic amyotrophic lateral sclerosis in Chinese men

2021 ◽  
Vol 49 (7) ◽  
pp. 030006052110332
Author(s):  
Zhiliang Fan ◽  
Hong Jiang ◽  
Xueqin Song ◽  
Yansu Guo ◽  
Xinying Tian
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Healthy Subjects ◽  
Chinese Population ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Glutathione S Transferase ◽  
Genotype Frequencies ◽  
Sporadic Als ◽  
Increased Risk ◽  
Chi Squared ◽  
Lateral Sclerosis

Objective To investigate whether GSTA1, GSTO2, and GSTZ1 are relevant to an increased risk of amyotrophic lateral sclerosis (ALS) in a Chinese population. Methods In this study, 143 sporadic ALS (sALS) patients (83 men, 60 women) and 210 age- and sex-matched healthy subjects were enrolled. Blood samples were collected by venipuncture. Genomic DNA was isolated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) according to the manufacturer’s instructions. The potential associations between ALS and GSTA1, GSTO2, and GSTZ1 polymorphisms were estimated using chi-squared analysis and unconditional logistic regression. Results The D allele and genotype frequencies of GSTO2 were increased in sALS patients compared with healthy subjects, indicating that the GSTO2 DD genotype was associated with an increased risk of sALS (odds ratio [OR] = 3.294, 95% confidence interval [CI] = 1.039–10.448). However, a significant association between the DD genotype and the risk of sALS was evident in men only (OR = 7.167, 95% CI = 1.381–37.202). Conclusion This study revealed that the D allele and genotype frequencies of GSTO2 were increased in sALS patients. The GSTO2 DD genotype was associated with an increased risk of sALS in men in a Chinese population.

scholarly journals Evidence for polygenic and oligogenic basis of Australian sporadic amyotrophic lateral sclerosis

2020 ◽  
pp. jmedgenet-2020-106866 ◽  
Author(s):  
Emily P McCann ◽  
Lyndal Henden ◽  
Jennifer A Fifita ◽  
Katharine Y Zhang ◽  
Natalie Grima ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Genetic Variation ◽  
Genetic Analysis ◽  
Genetic Variants ◽  
Age Of Onset ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Whole Genome ◽  
Identity By Descent ◽  
Sporadic Als ◽  
Lateral Sclerosis

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with phenotypic and genetic heterogeneity. Approximately 10% of cases are familial, while remaining cases are classified as sporadic. To date, >30 genes and several hundred genetic variants have been implicated in ALS.MethodsSeven hundred and fifty-seven sporadic ALS cases were recruited from Australian neurology clinics. Detailed clinical data and whole genome sequencing (WGS) data were available from 567 and 616 cases, respectively, of which 426 cases had both datasets available. As part of a comprehensive genetic analysis, 853 genetic variants previously reported as ALS-linked mutations or disease-associated alleles were interrogated in sporadic ALS WGS data. Statistical analyses were performed to identify correlation between clinical variables, and between phenotype and the number of ALS-implicated variants carried by an individual. Relatedness between individuals carrying identical variants was assessed using identity-by-descent analysis.ResultsForty-three ALS-implicated variants from 18 genes, including C9orf72, ATXN2, TARDBP, SOD1, SQSTM1 and SETX, were identified in Australian sporadic ALS cases. One-third of cases carried at least one variant and 6.82% carried two or more variants, implicating a potential oligogenic or polygenic basis of ALS. Relatedness was detected between two sporadic ALS cases carrying a SOD1 p.I114T mutation, and among three cases carrying a SQSTM1 p.K238E mutation. Oligogenic/polygenic sporadic ALS cases showed earlier age of onset than those with no reported variant.ConclusionWe confirm phenotypic associations among ALS cases, and highlight the contribution of genetic variation to all forms of ALS.

scholarly journals SMN1 copy number as a modifying factor of survival in Serbian patients with sporadic amyotrophic lateral sclerosis

2018 ◽  
Vol 146 (11-12) ◽  
pp. 646-652
Author(s):  
Milos Brkusanin ◽  
Irena Jeftovic-Velkova ◽  
Vladimir Jovanovic ◽  
Stojan Peric ◽  
Jovan Pesovic ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Copy Number ◽  
Rating Scale ◽  
Cox Regression ◽  
Diagnostic Delay ◽  
Susceptibility Genes ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Cox Regression Analysis ◽  
Sporadic Als ◽  
Lateral Sclerosis

Introduction/Objective. Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The majority of cases are apparently sporadic ALS (SALS) with variants in susceptibility genes or sometimes in high-risk ALS genes. Two ALS susceptibility genes are SMN1, whose functional loss causes spinal muscular atrophy (SMA), and a nearly identical SMN2 gene, which modulates SMA severity. In this study we examined the association of copy number variations (CNVs) of SMN1 and SMN2 genes and two additional genes, SERF1 and NAIP, residing in the same genomic region (i.e. 5q13.2 segmental duplication), with SALS in patients from Serbia. Methods. Multiplex ligation-dependent probe amplification was used to determine CNVs of each gene in a clinically well-characterised group of 153 Serbian SALS patients and 153 controls. Results. Individual association between SMN1, SMN2, SERF1 or NAIP CNVs and SALS susceptibility or survival was not found. Survival curves based on the multivariable Cox regression analysis showed that three SMN1 copies, lower ALS Functional Rating Scale Revised (ALSFRS-R) score at the time of diagnosis, faster decline of the ALSFRS-R score over time, and shorter diagnostic delay result in shorter survival of Serbian SALS patients. Conclusion. Clinical variables might be complemented with the SMN1 copy number to improve prediction of survival in Serbian SALS patients.

Progesterone and cortisol levels in sporadic amyotrophic lateral sclerosis (sALS): correlation with prognostic factors

2011 ◽  
Vol 6 (1) ◽  
Author(s):  
Gisella Gargiulo Monachelli ◽  
Maria Meyer ◽  
Gabriel Rodríguez ◽  
Laura Garay ◽  
Roberto E. Sica ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Prognostic Factors ◽  
Neurodegenerative Disorder ◽  
Neuronal Damage ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Sporadic Als ◽  
Bulbar Onset ◽  
Als Patients ◽  
Short Time ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder. Worse prognostic factors in ALS are: (a) advanced age, (b) bulbar onset, and (c) short time between onset and diagnosis. Progesterone (PROG) has been associated with neuroprotective and promyelinating activities in injury, ischemia and degeneration of the central and peripheral nervous system. Cortisol is connected to the response to stress situations and could contribute to neuronal damage. The goals of this study were: (i) to investigate whether PROG levels are modified by ALS prognostic factors and (ii) to determine whether cortisol follows the same pattern. We determined serum steroid levels in 27 patients with sporadic ALS (sALS) and 21 controls. Both steroid hormones showed significantly increased levels in ALS patients versus controls (mean±SEM: PROG ALS vs. control: 0.54±0.05 vs. 0.39±0.04 ng/mL, p<0.05; cortisol ALS vs. control: 17.02±1.60 vs. 11.83±1.38 μg/dL, p<0.05).

scholarly journals Amyotrophic lateral sclerosis: clinical analysis of 78 cases from Fortaleza (Northeastern Brazil)

1999 ◽  
Vol 57 (3B) ◽  
pp. 761-774 ◽  
Author(s):  
CARLOS M. DE CASTRO-COSTA ◽  
REINALDO B. ORIÁ ◽  
JOÃO A. MACHADO-FILHO ◽  
MARIA T. G. FRANCO ◽  
DÉBORA L. O. DINIZ ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Late Onset ◽  
Clinical Analysis ◽  
University Hospital ◽  
Northeastern Brazil ◽  
Anatomic Site ◽  
Muscle Enzymes ◽  
Sporadic Als ◽  
Diagnostic Certainty ◽  
Lateral Sclerosis

We report on the clinical characteristics of amyotrophic lateral sclerosis (ALS) in Fortaleza (Northeastern Brazil). For this, we analyzed retrospectively (from 1980 to 1999) 78 cases of ALS from the Service of Neurology of the University Hospital of Fortaleza diagnosed clinically and laboratorially (EMG, muscle biopsy, myelography, blood biochemistry, muscle enzymes and cranio-cervical X-ray). The results showed that they were mostly sporadic ALS (76/78), and they were divided into definite (n= 36), probable (n= 20), possible (n= 15) and suspected (n= 7), according to the level of diagnostic certainty. They were also subdivided into juvenile (n= 17), early-onset adult (n= 18), age-specific (n= 39) and late-onset (n= 4) groups. Clinically, they presented as initials symptoms, principally, asymmetrical (30/78) and symmetrical (24/78) weakness of extremities, besides bulbar signs, fasciculations, and atrophy. Curiously, pain as first symptom occurred in an expressive fashion (17/78). The predominant initial anatomic site, in this series, was the spinal cord, and mainly affecting the arms. As to the symptom accrual from region to region, this occurs more quickly in contiguous areas, and fasciculations are predominant when bulbar region was associated.

scholarly journals Splicing Players Are Differently Expressed in Sporadic Amyotrophic Lateral Sclerosis Molecular Clusters and Brain Regions

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 159 ◽  
Author(s):  
Valentina La Cognata ◽  
Giulia Gentile ◽  
Eleonora Aronica ◽  
Sebastiano Cavallaro
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Interactions ◽  
Brain Regions ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Splicing Factors ◽  
Granule Formation ◽  
Disease States ◽  
Sporadic Als ◽  
Genes Encoding ◽  
Lateral Sclerosis

Splicing is a tightly orchestrated process by which the brain produces protein diversity over time and space. While this process specializes and diversifies neurons, its deregulation may be responsible for their selective degeneration. In amyotrophic lateral sclerosis (ALS), splicing defects have been investigated at the singular gene level without considering the higher-order level, involving the entire splicing machinery. In this study, we analyzed the complete spectrum (396) of genes encoding splicing factors in the motor cortex (41) and spinal cord (40) samples from control and sporadic ALS (SALS) patients. A substantial number of genes (184) displayed significant expression changes in tissue types or disease states, were implicated in distinct splicing complexes and showed different topological hierarchical roles based on protein–protein interactions. The deregulation of one of these splicing factors has a central topological role, i.e., the transcription factor YBX1, which might also have an impact on stress granule formation, a pathological marker associated with ALS.

scholarly journals Monozygotic twin pairs discordant for amyotrophic lateral sclerosis carry both common and unique epigenetic differences relevant to disease

2016 ◽  
Author(s):  
Paul E Young ◽  
Stephen Kum Jew ◽  
Michael E Buckland ◽  
Roger Pamphlett ◽  
Catherine M Suter
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Large Scale ◽  
Cytosine Methylation ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Monozygotic Twin ◽  
Sporadic Als ◽  
High Heritability ◽  
Als Patients ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a devastating late-onset neurodegenerative disorder in which only a small proportion of patients carry an identifiable causative genetic lesion. Despite high heritability estimates, a genetic etiology for most sporadic ALS remains elusive. Here we report the epigenetic profiling of five monozygotic twin pairs discordant for ALS in whom previous genome sequencing excluded a genetic basis for their disease discordance. By studying cytosine methylation patterns in peripheral blood DNA we identified thousands of large between-twin differences at individual CpGs. While the specific sites of difference were largely idiosyncratic to a twin pair, a proportion (involving GABA signalling) were common to all affected individuals. In both instances the differences occurred within genes and pathways related to neurobiological function and dysfunction. Our findings reveal widespread changes in epigenetic marks in ALS patients, consistent with an epigenetic contribution to disease. These findings may be exploited to develop blood-based biomarkers of ALS and develop further insight into disease pathogenesis. We expect that our findings will provide a useful point of reference for further large scale studies of sporadic ALS.

scholarly journals MicroRNA-5572 Is a Novel MicroRNA-Regulating SLC30A3 in Sporadic Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 21 (12) ◽  
pp. 4482
Author(s):  
Hisaka Kurita ◽  
Saori Yabe ◽  
Tomoyuki Ueda ◽  
Masatoshi Inden ◽  
Akiyoshi Kakita ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Target Gene ◽  
Target Genes ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Novel Mirna ◽  
Sporadic Als ◽  
Candidate Target ◽  
Candidate Target Gene ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease caused by the loss of motor neurons. Although the pathogenesis of sporadic ALS (sALS) remains unclear, it has recently been suggested that disorders of microRNA (miRNA) may be involved in neurodegenerative conditions. The purpose of this study was to investigate miRNA levels in sALS and the target genes of miRNA. Microarray and real-time RT-PCR analyses revealed significantly-decreased levels of miR-139-5p and significantly increased levels of miR-5572 in the spinal cords of sALS patients compared with those in controls. We then focused on miR-5572, which has not been reported in ALS, and determined its target gene. By using TargetScan, we predicted SLC30A3 as the candidate target gene of miR-5572. In a previous study, we found decreased SLC30A3 levels in the spinal cords of sALS patients. We revealed that SLC30A3 was regulated by miR-5572. Taken together, these results demonstrate that the level of novel miRNA miR-5572 is increased in sALS and that SLC30A3 is one of the target genes regulated by miR-5572.

scholarly journals Wild-type Cu/Zn-superoxide dismutase is misfolded in cerebrospinal fluid of sporadic amyotrophic lateral sclerosis

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Eiichi Tokuda ◽  
Yo-ichi Takei ◽  
Shinji Ohara ◽  
Noriko Fujiwara ◽  
Isao Hozumi ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cerebrospinal Fluid ◽  
Superoxide Dismutase ◽  
Neurodegenerative Diseases ◽  
Sandwich Elisa ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Wild Type ◽  
Sporadic Als ◽  
Misfolded Sod1 ◽  
Lateral Sclerosis

Abstract Background A subset of familial forms of amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene coding Cu/Zn-superoxide dismutase (SOD1). Mutant SOD1 proteins are susceptible to misfolding and abnormally accumulated in spinal cord, which is most severely affected in ALS. It, however, remains quite controversial whether misfolding of wild-type SOD1 is involved in more prevalent sporadic ALS (sALS) cases without SOD1 mutations. Methods Cerebrospinal fluid (CSF) from patients including sALS as well as several other neurodegenerative diseases and non-neurodegenerative diseases was examined with an immunoprecipitation assay and a sandwich ELISA using antibodies specifically recognizing misfolded SOD1. Results We found that wild-type SOD1 was misfolded in CSF from all sALS cases examined in this study. The misfolded SOD1 was also detected in CSF from a subset of Parkinson’s disease and progressive supranuclear palsy, albeit with smaller amounts than those in sALS. Furthermore, the CSF samples containing the misfolded SOD1 exhibited significant toxicity toward motor neuron-like NSC-34 cells, which was ameliorated by removal of the misfolded wild-type SOD1 with immunoprecipitation. Conclusions Taken together, we propose that misfolding of wild-type SOD1 in CSF is a common pathological process of ALS cases regardless of SOD1 mutations.

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