ABSTRACT
SignificanceThe GGGGCC hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 (C9orf72) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS). Despite myriad studies on the toxic effects of poly-dipeptides produced from the C9orf72 repeats, the mechanisms underlying the selective hyperexcitability of motor cortex that characterizes the early stages of C9orf72 ALS patients remain elusive. Here, we show that the proline-arginine poly-dipeptides cause hyperexcitability in cortical motor neurons by increasing persistent sodium currents conducted by the Nav1.2/ß4 sodium channel complex, which is highly expressed in the motor cortex. These findings provide the basis for understanding how the C9orf72 mutation causes motor neuron hyperactivation that can lead to the motor neuron death in C9orf72 ALS.
Subject(s)
Amyotrophic Lateral Sclerosis/etiology , Amyotrophic Lateral Sclerosis/metabolism , C9orf72 Protein/genetics , Dipeptides/genetics , Hyperkinesis/genetics , Motor Neurons/metabolism , Amyotrophic Lateral Sclerosis/pathology , Arginine , Cerebral Cortex/metabolism , Cerebral Cortex/physiopathology , Dipeptides/metabolism , Disease Susceptibility , Evoked Potentials, Motor , Genetic Predisposition to Disease , Humans , Phenotype , Proline , Sodium/metabolismABSTRACT
Expansion of the hexanucleotide repeat (HR) in the first intron of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in Caucasians. All C9orf72-ALS/FTD patients share a common risk (R) haplotype. To study C9orf72 expression and splicing from the mutant R allele compared to the complementary normal allele in ALS/FTD patients, we initially created a detailed molecular map of the single nucleotide polymorphism (SNP) signature and the HR length of the various C9orf72 haplotypes in Caucasians. We leveraged this map to determine the allelic origin of transcripts per patient, and decipher the effects of pathological and normal HR lengths on C9orf72 expression and splicing. In C9orf72 ALS patients' cells, the HR expanded allele, compared to non-R allele, was associated with decreased levels of a downstream initiated transcript variant and increased levels of transcripts initiated upstream of the HR. HR expanded R alleles correlated with high levels of unspliced intron 1 and activation of cryptic donor splice sites along intron 1. Retention of intron 1 was associated with sequential intron 2 retention. The SNP signature of C9orf72 haplotypes described here enables allele-specific analysis of transcriptional products and may pave the way to allele-specific therapeutic strategies.
Subject(s)
Alleles , C9orf72 Protein/genetics , Disease Susceptibility , Gene Expression Regulation , Haplotypes , RNA Splicing , Amyotrophic Lateral Sclerosis/diagnosis , Amyotrophic Lateral Sclerosis/etiology , Frontotemporal Dementia/diagnosis , Frontotemporal Dementia/etiology , Genotype , Humans , Introns , Polymorphism, Single Nucleotide , Quantitative Trait Loci , RNA Splice SitesABSTRACT
Many pathogenetic mechanisms have been proposed for amyotrophic lateral sclerosis (ALS). Recently, there have been emerging suggestions of a possible role for the gut microbiota. Gut microbiota have a range of functions and could influence ALS by several mechanisms. Here, we review the possible role of gut-derived neurotoxins/excitotoxins. We review the evidence of gut symptoms and gut dysbiosis in ALS. We then examine a possible role for gut-derived toxins by reviewing the evidence that these molecules are toxic to the central nervous system, evidence of their association with ALS, the existence of biochemical pathways by which these molecules could be produced by the gut microbiota and existence of mechanisms of transport from the gut to the blood and brain. We then present evidence that there are increased levels of these toxins in the blood of some ALS patients. We review the effects of therapies that attempt to alter the gut microbiota or ameliorate the biochemical effects of gut toxins. It is possible that gut dysbiosis contributes to elevated levels of toxins and that these could potentially contribute to ALS pathogenesis, but more work is required.
Subject(s)
Amyotrophic Lateral Sclerosis , Gastrointestinal Microbiome , Humans , Amyotrophic Lateral Sclerosis/etiology , Dysbiosis/etiology , Gastrointestinal Microbiome/physiology , BrainABSTRACT
Given the increasing trend of aging population in the world, neurodegenerative diseases (NDDs), a common type of diseases that mostly occur in the elderly, have attracted much more attention. It has been shown that tumor necrosis factor receptor-associated factor 6 (TRAF6) is involved in the regulation of neuroinflammation, an important pathological feature of NDDs, and affects the occurrence and development of NDDs. Most importantly, the regulatory effect of TRAF6 is related to its ubiquitination. Therefore, in the present paper, the molecular structure, biological function, and ubiquitination mechanism of TRAF6, and its relationship with some common NDDs, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, were analyzed and summarized. The possible molecular mechanisms by which TRAF6 regulates the occurrence of NDDs were also elucidated, providing a theoretical basis for exploring the etiology and treatment of NDDs.
Subject(s)
Neurodegenerative Diseases , TNF Receptor-Associated Factor 6 , Humans , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/etiology , TNF Receptor-Associated Factor 6/metabolism , TNF Receptor-Associated Factor 6/genetics , TNF Receptor-Associated Factor 6/physiology , Ubiquitination , Alzheimer Disease/metabolism , Alzheimer Disease/etiology , Parkinson Disease/metabolism , Parkinson Disease/physiopathology , Animals , Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/physiopathology , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/etiology , Multiple Sclerosis/metabolism , Multiple Sclerosis/physiopathology , Multiple Sclerosis/etiologyABSTRACT
Studies suggest a link between particulate matter less than or equal to 2.5 µm in diameter (PM2.5) and amyotrophic lateral sclerosis (ALS), but to our knowledge critical exposure windows have not been examined. We performed a case-control study in the Danish population spanning the years 1989-2013. Cases were selected from the Danish National Patient Registry based on International Classification of Diseases codes. Five controls were randomly selected from the Danish Civil Registry and matched to a case on vital status, age, and sex. PM2.5 concentration at residential addresses was assigned using monthly predictions from a dispersion model. We used conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for confounding. We evaluated exposure to averaged PM2.5 concentrations 12-24 months, 2-6 years, and 2-11 years pre-ALS diagnosis; annual lagged exposures up to 11 years prediagnosis; and cumulative associations for exposure in lags 1-5 years and 1-10 years prediagnosis, allowing for varying association estimates by year. We identified 3,983 cases and 19,915 controls. Cumulative exposure to PM2.5 in the period 2-6 years prediagnosis was associated with ALS (OR = 1.06, 95% CI: 0.99, 1.13). Exposures in the second, third, and fourth years prediagnosis were individually associated with higher odds of ALS (e.g., for lag 1, OR = 1.04, 95% CI: 1.00, 1.08). Exposure to PM2.5 within 6 years before diagnosis may represent a critical exposure window for ALS.
Subject(s)
Air Pollutants , Air Pollution , Amyotrophic Lateral Sclerosis , Humans , Case-Control Studies , Amyotrophic Lateral Sclerosis/epidemiology , Amyotrophic Lateral Sclerosis/etiology , Risk Factors , Particulate Matter/adverse effects , Particulate Matter/analysis , Denmark/epidemiology , Environmental Exposure/adverse effects , Air Pollutants/adverse effects , Air Pollutants/analysis , Air Pollution/adverse effectsABSTRACT
C9orf72 ALS/FTD patients show remarkable clinical heterogeneity, but the complex biology of the repeat expansion mutation has limited our understanding of the disease. BAC transgenic mice were used to better understand the molecular mechanisms and repeat length effects of C9orf72 ALS/FTD. Genetic analyses of these mice demonstrate that the BAC transgene and not integration site effects cause ALS/FTD phenotypes. Transcriptomic changes in cell proliferation, inflammation and neuronal pathways are found late in disease and alternative splicing changes provide early molecular markers that worsen with disease progression. Isogenic sublines of mice with 800, 500 or 50 G4C2 repeats generated from the single-copy C9-500 line show longer repeats result in earlier onset, increased disease penetrance and increased levels of RNA foci and dipeptide RAN protein aggregates. These data demonstrate G4C2 repeat length is an important driver of disease and identify alternative splicing changes as early biomarkers of C9orf72 ALS/FTD.
Subject(s)
Alternative Splicing , Amyotrophic Lateral Sclerosis/pathology , C9orf72 Protein/metabolism , DNA Repeat Expansion , Disease Models, Animal , Frontotemporal Dementia/pathology , Penetrance , Amyotrophic Lateral Sclerosis/etiology , Amyotrophic Lateral Sclerosis/metabolism , Animals , C9orf72 Protein/genetics , Frontotemporal Dementia/etiology , Frontotemporal Dementia/metabolism , Humans , Mice , Mice, Transgenic , Mutation , PhenotypeABSTRACT
Objective - to identify risk factors in patients diagnosed with Amyotrophic Lateral Sclerosis in Georgia directed to The First University Clinic of TSMU and P. Sarajishvili Institute of Neurology. Totally 53 patients, aged 24 to 82 years, were investigated with Amyotrophic Lateral Sclerosis (ALS), defined by "Gold Coast " criteria. We have used the Questionnaire for Environmental Exposures, Toxins, and Neurological diseases developed by Dartmouth-Hitchcock Medical center to identify risk factors, and categorized patients according to the place of settlement and environmental hazards. The control consisted of age and sex matched 50 healthy individuals. The brain was visualized by MRI (1.5T), and Electromyography (EMG) was performed on all patients. ALS risk was higher among those ever holding a job in mechanics, painting, or construction (p<0.05), head trauma or concussion that caused a "blackout" or loss of consciousness was associated with a higher risk of ALS (p<0.01). Demographically more ALS cases were found in Tbilisi and Imereti, compared to other regions (p<0.05). According to our research on Georgian ALS cases, several occupational jobs, Head trauma is associated with developing ALS in Georgia, Research is needed to identify environmental risk factors attributing to higher rates of ALS in Tbilisi and Imereti.
Subject(s)
Amyotrophic Lateral Sclerosis , Craniocerebral Trauma , Humans , Amyotrophic Lateral Sclerosis/epidemiology , Amyotrophic Lateral Sclerosis/etiology , Amyotrophic Lateral Sclerosis/diagnosis , Georgia (Republic)/epidemiology , Risk Factors , Environmental Exposure/adverse effects , Craniocerebral Trauma/complicationsABSTRACT
BACKGROUND: Experimental observations have suggested a role of infection in the etiology of neurodegenerative disease. In human studies, however, it is difficult to disentangle whether infection is a risk factor or rather a comorbidity or secondary event of neurodegenerative disease. To this end, we examined the risk of 3 most common neurodegenerative diseases in relation to previous inpatient or outpatient episodes of hospital-treated infections. METHODS AND FINDINGS: We performed a nested case-control study based on several national registers in Sweden. Cases were individuals newly diagnosed with Alzheimer's disease (AD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS) during 1970 to 2016 in Sweden, identified from the National Patient Register. For each case, 5 controls individually matched to the case on sex and year of birth were randomly selected from the general population. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) with adjustment for potential confounders, including sex, year of birth, area of residence, educational attainment, family history of neurodegenerative disease, and Charlson comorbidity index. Infections experienced within 5 years before diagnosis of neurodegenerative disease were excluded to reduce the influence of surveillance bias and reverse causation. The analysis included 291,941 AD cases (median age at diagnosis: 76.2 years; male: 46.6%), 103,919 PD cases (74.3; 55.1%), and 10,161 ALS cases (69.3; 56.8%). A hospital-treated infection 5 or more years earlier was associated with an increased risk of AD (OR = 1.16, 95% CI: 1.15 to 1.18, P < 0.001) and PD (OR = 1.04, 95% CI: 1.02 to 1.06, P < 0.001). Similar results were observed for bacterial, viral, and other infections and among different sites of infection including gastrointestinal and genitourinary infections. Multiple infections before age 40 conveyed the greatest risk of AD (OR = 2.62, 95% CI: 2.52 to 2.72, P < 0.001) and PD (OR = 1.41, 95% CI: 1.29 to 1.53, P < 0.001). The associations were primarily due to AD and PD diagnosed before 60 years (OR = 1.93, 95% CI: 1.89 to 1.98 for AD, P < 0.001; OR = 1.29, 95% CI: 1.22 to 1.36 for PD, P < 0.001), whereas no association was found for those diagnosed at 60 years or older (OR = 1.00, 95% CI: 0.98 to 1.01 for AD, P = 0.508; OR = 1.01, 95% CI: 0.99 to 1.03 for PD, P = 0.382). No association was observed for ALS (OR = 0.97, 95% CI: 0.92 to 1.03, P = 0.384), regardless of age at diagnosis. Excluding infections experienced within 10 years before diagnosis of neurodegenerative disease confirmed these findings. Study limitations include the potential misclassification of hospital-treated infections and neurodegenerative diseases due to incomplete coverage of the National Patient Register, as well as the residual confounding from unmeasured risk or protective factors for neurodegenerative diseases. CONCLUSIONS: Hospital-treated infections, especially in early- and mid-life, were associated with an increased risk of AD and PD, primarily among AD and PD cases diagnosed before 60 years. These findings suggest that infectious events may be a trigger or amplifier of a preexisting disease process, leading to clinical onset of neurodegenerative disease at a relatively early age. However, due to the observational nature of the study, these results do not formally prove a causal link.
Subject(s)
Alzheimer Disease , Amyotrophic Lateral Sclerosis , Cross Infection , Neurodegenerative Diseases , Parkinson Disease , Adult , Alzheimer Disease/epidemiology , Alzheimer Disease/etiology , Amyotrophic Lateral Sclerosis/epidemiology , Amyotrophic Lateral Sclerosis/etiology , Case-Control Studies , Hospitals , Humans , Male , Parkinson Disease/epidemiology , Parkinson Disease/etiology , Sweden/epidemiologyABSTRACT
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Limited evidence suggests ALS diagnosis may be associated with air pollution exposure and specifically traffic-related pollutants. METHODS: In this population-based case-control study, we used 3,937 ALS cases from the Danish National Patient Register diagnosed during 1989-2013 and matched on age, sex, year of birth, and vital status to 19,333 population-based controls free of ALS at index date. We used validated predictions of elemental carbon (EC), nitrogen oxides (NO x ), carbon monoxide (CO), and fine particles (PM 2.5 ) to assign 1-, 5-, and 10-year average exposures pre-ALS diagnosis at study participants' present and historical residential addresses. We used an adjusted Bayesian hierarchical conditional logistic model to estimate individual pollutant associations and joint and average associations for traffic-related pollutants (EC, NO x , CO). RESULTS: For a standard deviation (SD) increase in 5-year average concentrations, EC (SD = 0.42 µg/m 3 ) had a high probability of individual association with increased odds of ALS (11.5%; 95% credible interval [CrI] = -1.0%, 25.6%; 96.3% posterior probability of positive association), with negative associations for NO x (SD = 20 µg/m 3 ) (-4.6%; 95% CrI = 18.1%, 8.9%; 27.8% posterior probability of positive association), CO (SD = 106 µg/m 3 ) (-3.2%; 95% CrI = 14.4%, 10.0%; 26.7% posterior probability of positive association), and a null association for nonelemental carbon fine particles (non-EC PM 2.5 ) (SD = 2.37 µg/m 3 ) (0.7%; 95% CrI = 9.2%, 12.4%). We found no association between ALS and joint or average traffic pollution concentrations. CONCLUSIONS: This study found high probability of a positive association between ALS diagnosis and EC concentration. Further work is needed to understand the role of traffic-related air pollution in ALS pathogenesis.
Subject(s)
Air Pollutants , Air Pollution , Amyotrophic Lateral Sclerosis , Neurodegenerative Diseases , Air Pollutants/analysis , Air Pollutants/toxicity , Air Pollution/adverse effects , Air Pollution/analysis , Amyotrophic Lateral Sclerosis/diagnosis , Amyotrophic Lateral Sclerosis/epidemiology , Amyotrophic Lateral Sclerosis/etiology , Bayes Theorem , Carbon Monoxide/adverse effects , Case-Control Studies , Denmark/epidemiology , Environmental Exposure/adverse effects , Environmental Exposure/analysis , Humans , Nitrogen Oxides/analysis , Particulate Matter/adverse effects , Particulate Matter/analysis , Vehicle Emissions/analysis , Vehicle Emissions/toxicityABSTRACT
OBJECTIVE: Metals have been suggested as a risk factor for amyotrophic lateral sclerosis (ALS), but only retrospective studies are available to date. We compared metal levels in prospectively collected blood samples from ALS patients and controls, to explore whether metals are associated with ALS mortality. METHODS: A nested ALS case-control study was conducted within the prospective EPIC (European Prospective Investigation into Cancer and Nutrition) cohort. Cases were identified through death certificates. We analyzed metal levels in erythrocyte samples obtained at recruitment, as a biomarker for metal exposure from any source. Arsenic, cadmium, copper, lead, manganese, mercury, selenium, and zinc concentrations were measured by inductively coupled plasma-mass spectrometry. To estimate ALS risk, we applied conditional logistic regression models. RESULTS: The study population comprised 107 cases (65% female) and 319 controls matched for age, sex, and study center. Median time between blood collection and ALS death was 8 years (range = 1-15). Comparing the highest with the lowest tertile, cadmium (odds ratio [OR] = 2.04, 95% confidence interval [CI] = 1.08-3.87) and lead (OR = 1.89, 95% CI = 0.97-3.67) concentrations suggest associations with increased ALS risk. Zinc was associated with a decreased risk (OR = 0.50, 95% CI = 0.27-0.94). Associations for cadmium and lead remained when limiting analyses to noncurrent smokers. INTERPRETATION: This is the first study to compare metal levels before disease onset, minimizing reverse causation. The observed associations suggest that cadmium, lead, and zinc may play a role in ALS etiology. Cadmium and lead possibly act as intermediates on the pathway from smoking to ALS. ANN NEUROL 20209999:n/a-n/a.
Subject(s)
Amyotrophic Lateral Sclerosis/blood , Amyotrophic Lateral Sclerosis/etiology , Environmental Exposure , Mercury/blood , Adult , Aged , Cohort Studies , Female , Humans , Male , Middle Aged , Prospective Studies , Retrospective Studies , RiskABSTRACT
OBJECTIVE: The only identified cause of amyotrophic lateral sclerosis (ALS) are mutations in a number of genes found in familial cases but also in sporadic cases. De novo mutations occurring in a parental gonadal cell, in the zygote or postzygotic during embryonal development can result in an apparently sporadic/isolated case of ALS later in life. We searched for de novo mutations in SOD1 as a cause of ALS. METHODS: We analysed peripheral-blood exome, genome and Sanger sequencing to identify deleterious mutations in SOD1 in 4000 ALS patients from Germany, South Korea and Sweden. Parental kinship was confirmed using highly polymorphic microsatellite markers across the genome. Medical genealogical and clinical data were reviewed and compared with the literature. RESULTS: We identified four sporadic ALS cases with de novo mutations in SOD1. They aggregate in hot-spot codons earlier found mutated in familial cases. Their phenotypes match closely what has earlier been reported in familial cases with pathogenic mutations in SOD1. We also encountered familial cases where de novo mutational events in recent generations may have been involved. CONCLUSIONS: De novo mutations are a cause of sporadic ALS and may also be underpinning smaller families with few affected ALS cases. It was not possible to ascertain if the origin of the de novo mutations was parental germline, zygotic or postzygotic during embryonal development. All ALS patients should be offered genetic counselling and genetic screening, the challenges of variant interpretation do not outweigh the potential benefits including earlier confirmed diagnosis and possible bespoken therapy.
Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Superoxide Dismutase-1/genetics , Adult , Amyotrophic Lateral Sclerosis/etiology , Female , Genetic Association Studies , Genetic Testing , Germany , Humans , Longitudinal Studies , Male , Mutation , Phenotype , RNA-Binding Protein FUS/genetics , Republic of Korea , Sweden , Young AdultABSTRACT
All proteins have the inherent ability to undergo transformation from their native structure to a ß sheet rich fibrillar structure, called amyloid when subjected to specific conditions. Proteins with a high propensity to form amyloid fibrils have been implicated in a variety of disorders like Alzheimer's disease, Parkinson's disease, Type II diabetes, Amyotrophic Lateral Sclerosis (ALS) and prion diseases. Among the various critical factors that modulate the process of amyloid formation, disulfide bonds have been identified as one of the key determinants of amyloid propensity in proteins. Studies have shown that intra-molecular disulfide bonds impart stability to the native structure of a protein and decrease the tendency for amyloid aggregation, whereas intermolecular disulfide bonds aid in the process of aggregation. In this review, we will analyze the varying effects of both intra as well as inter-molecular disulfide bonds on the amyloid aggregation propensities of a few proteins associated with amyloid disorders.
Subject(s)
Amyloidogenic Proteins/chemistry , Amyloidosis/etiology , Disulfides/chemistry , Alzheimer Disease/etiology , Amyloidogenic Proteins/metabolism , Amyotrophic Lateral Sclerosis/etiology , Diabetes Mellitus, Type 2/etiology , Disulfides/metabolism , Humans , Insulin/chemistry , Intramolecular Lyases/chemistry , Models, Molecular , Phosphatidylinositols/metabolism , Prion Diseases/ethnology , Protein Aggregates , Protein Binding , Protein Conformation , Structure-Activity RelationshipABSTRACT
The mitochondria-associated membrane (MAM) is a functional subdomain of the endoplasmic reticulum membrane that tethers to the mitochondrial outer membrane and is essential for cellular homeostasis. A defect in MAM is involved in various neurological diseases, including amyotrophic lateral sclerosis (ALS). Recently, we and others reported that MAM was disrupted in the models expressing several ALS-linked genes, including SOD1, SIGMAR1, VAPB, TARDBP, and FUS, suggesting that MAM disruption is deeply involved in the pathomechanism of ALS. However, it is still uncertain whether MAM disruption is a common pathology in ALS, mainly due to the absence of a simple, quantitative tool for monitoring the status of MAM. In this study, to examine the effects of various ALS-causative genes on MAM, we created the following two novel MAM reporters: MAMtracker-Luc and MAMtracker-Green. The MAMtrackers could detect MAM disruption caused by suppression of SIGMAR1 or the overexpression of ALS-linked mutant SOD1 in living cells. Moreover, the MAMtrackers have an advantage in their ability to monitor reversible changes in the MAM status induced by nutritional conditions. We used the MAMtrackers with an expression plasmid library of ALS-causative genes and noted that 76% (16/21) of the genes altered MAM integrity. Our results suggest that MAM disruption is a common pathological feature in ALS. Furthermore, we anticipate our MAMtrackers, which are suitable for high-throughput assays, to be valuable tools to understand MAM dynamics.
Subject(s)
Amyotrophic Lateral Sclerosis/pathology , Mitochondria/pathology , Mitochondrial Membranes/pathology , Mitochondrial Proteins/metabolism , Mutation , Neuroblastoma/pathology , Amyotrophic Lateral Sclerosis/etiology , Amyotrophic Lateral Sclerosis/metabolism , Animals , Humans , Mice , Mitochondria/metabolism , Mitochondrial Membranes/metabolism , Mitochondrial Proteins/genetics , Neuroblastoma/genetics , Neuroblastoma/metabolismABSTRACT
Amyotrophic lateral sclerosis (ALS) is a grievous neurodegenerative disease whose survival is limited to only a few years. In spite of intensive research to discover the underlying mechanisms, the results are fairly inconclusive. Multiple hypotheses have been regarded, including genetic, molecular, and cellular processes. Notably, oxidative stress has been demonstrated to play a crucial role in ALS pathogenesis. In addition to already recognized and exhaustively studied genetic mutations involved in oxidative stress production, exposure to various environmental factors (e.g., electromagnetic fields, solvents, pesticides, heavy metals) has been suggested to enhance oxidative damage. This review aims to describe the main processes influenced by the most frequent genetic mutations and environmental factors concurring in oxidative stress occurrence in ALS and the potential therapeutic molecules capable of diminishing the ALS related pro-oxidative status.
Subject(s)
Amyotrophic Lateral Sclerosis , Neurodegenerative Diseases , Pesticides , Amyotrophic Lateral Sclerosis/etiology , Electromagnetic Fields , Humans , Neurodegenerative Diseases/complications , Oxidative StressABSTRACT
The pathoetiology and pathophysiology of motor neuron loss in amyotrophic lateral sclerosis (ALS) are still to be determined, with only a small percentage of ALS patients having a known genetic risk factor. The article looks to integrate wider bodies of data on the biological underpinnings of ALS, highlighting the integrative role of alterations in the mitochondrial melatonergic pathways and systemic factors regulating this pathway across a number of crucial hubs in ALS pathophysiology, namely glia, gut, and the muscle/neuromuscular junction. It is proposed that suppression of the mitochondrial melatonergic pathway underpins changes in muscle brain-derived neurotrophic factor, and its melatonergic pathway mimic, N-acetylserotonin, leading to a lack of metabolic trophic support at the neuromuscular junction. The attenuation of the melatonergic pathway in astrocytes prevents activation of toll-like receptor agonists-induced pro-inflammatory transcription factors, NF-kB, and yin yang 1, from having a built-in limitation on inflammatory induction that arises from their synchronized induction of melatonin release. Such maintained astrocyte activation, coupled with heightened microglia reactivity, is an important driver of motor neuron susceptibility in ALS. Two important systemic factors, gut dysbiosis/permeability and pineal melatonin mediate many of their beneficial effects via their capacity to upregulate the mitochondrial melatonergic pathway in central and systemic cells. The mitochondrial melatonergic pathway may be seen as a core aspect of cellular function, with its suppression increasing reactive oxygen species (ROS), leading to ROS-induced microRNAs, thereby altering the patterning of genes induced. It is proposed that the increased occupational risk of ALS in farmers, gardeners, and sportsmen and women is intimately linked to exposure, whilst being physically active, to the widely used glyphosate-based herbicides. This has numerous research and treatment implications.
Subject(s)
Amyotrophic Lateral Sclerosis , Gastrointestinal Microbiome , Herbicides , Melatonin , Humans , Amyotrophic Lateral Sclerosis/etiology , Amyotrophic Lateral Sclerosis/physiopathology , Astrocytes/metabolism , Melatonin/metabolism , Muscles/metabolism , Reactive Oxygen Species , Herbicides/toxicity , GlyphosateABSTRACT
Protein aggregation is a common feature in prominent neurodegenerative diseases, usually thought to be due to the assembly of a single peptide or protein. Recent studies have challenged this notion and suggested several proteins may be involved in promoting and amplifying disease. For example, the TDP-43 protein associated with Amyotrophic Lateral Sclerosis has been found in the brain along with Aß assemblies associated with Alzheimer's disease, and those patients that show the presence of TDP-43 are 10 times more likely to demonstrate cognitive impairment compared to TDP-43-negative Alzheimer's patients. Here we examine the interactions between the amyloidogenic core of TDP-43, TDP-43307-319, and a neurotoxic physiologically observed fragment of Aß, Aß25-35. Utilizing ion mobility mass spectrometry in concert with atomic force microscopy and molecular dynamics simulations, we investigate which oligomers are involved in seeding aggregation across these two different protein systems and gain insight into which structures initiate and result from these interactions. Studies were conducted by mixing Aß25-35 with the toxic wild type TDP-43307-319 peptide and with the nontoxic synthetic TDP-43307-319 mutant, G314V. Our findings identify a strong catalytic effect of TDP-43307-319 WT monomer in the acceleration of Aß25-35 aggregation to its toxic cylindrin and ß barrel forms. This observation is unprecedented in both its speed and specificity. Interestingly, the nontoxic G314V mutant of TDP-43307-319 and dimers or higher order oligomers of WT TDP-43307-319 do not promote aggregation of Aß25-35 but rather dissociate preformed toxic higher order oligomers of Aß25-35. Reasons for these very different behaviors are reported.
Subject(s)
Amyloid beta-Peptides/metabolism , DNA-Binding Proteins/metabolism , Peptide Fragments/metabolism , Alzheimer Disease/etiology , Amyloid beta-Peptides/chemistry , Amyotrophic Lateral Sclerosis/etiology , Binding Sites , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/genetics , Humans , Hydrogen Bonding , Mass Spectrometry/methods , Microscopy, Atomic Force , Molecular Dynamics Simulation , Mutation , Peptide Fragments/chemistry , Protein Binding/genetics , Protein Multimerization/geneticsABSTRACT
Observational studies have shown alcohol drinking behaviors may be associated with the risk of amyotrophic lateral sclerosis (ALS), but contradictory findings have emerged, and whether such an association is causal is unclear. We here investigate the causal relationship between alcohol consumption and ALS. By leveraging instruments from large-scale genome-wide association studies, we performed a comprehensive Mendelian randomization analysis and found alcohol consumption was causally associated with ALS, leading to â¼1.5-fold (95% confidence interval = 1.4-3.4) higher risk of ALS for each â¼10g/day increase in alcohol intake. Our findings suggest accumulative alcohol consumption may serve as a crucial risk factor in the pathogenesis of ALS. ANN NEUROL 2020 ANN NEUROL 2020;88:195-198.
Subject(s)
Alcohol Drinking/adverse effects , Amyotrophic Lateral Sclerosis/etiology , Female , Genome-Wide Association Study , Humans , Male , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide , Risk FactorsABSTRACT
Pathological changes involving TDP-43 protein ('TDP-43 proteinopathy') are typical for several neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD). FTLD-TDP cases are characterized by increased binding of TDP-43 to an abundant lncRNA, NEAT1, in the cortex. However it is unclear whether enhanced TDP-43-NEAT1 interaction represents a protective mechanism. We show that accumulation of human TDP-43 leads to upregulation of the constitutive NEAT1 isoform, NEAT1_1, in cultured cells and in the brains of transgenic mice. Further, we demonstrate that overexpression of NEAT1_1 ameliorates TDP-43 toxicity in Drosophila and yeast models of TDP-43 proteinopathy. Thus, NEAT1_1 upregulation may be protective in TDP-43 proteinopathies affecting the brain. Approaches to boost NEAT1_1 expression in the CNS may prove useful in the treatment of these conditions.
Subject(s)
Amyotrophic Lateral Sclerosis/prevention & control , Brain/metabolism , DNA-Binding Proteins/toxicity , Frontotemporal Dementia/prevention & control , Neuroblastoma/prevention & control , RNA, Long Noncoding/genetics , TDP-43 Proteinopathies/prevention & control , Amyotrophic Lateral Sclerosis/etiology , Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/pathology , Animals , Brain/pathology , Disease Models, Animal , Drosophila melanogaster , Frontotemporal Dementia/etiology , Frontotemporal Dementia/metabolism , Frontotemporal Dementia/pathology , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neuroblastoma/etiology , Neuroblastoma/metabolism , Neuroblastoma/pathology , RNA, Long Noncoding/administration & dosage , Saccharomyces cerevisiae , TDP-43 Proteinopathies/etiology , TDP-43 Proteinopathies/metabolism , TDP-43 Proteinopathies/pathologyABSTRACT
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder of the motor system. The etiology is still unknown and the pathogenesis remains unclear. ALS is familial in the 10% of cases with a Mendelian pattern of inheritance. In the remaining sporadic cases, a multifactorial origin is supposed in which several predisposing genes interact with environmental factors. The etiological role of environmental factors, such as pesticides, exposure to electromagnetic fields, and metals has been frequently investigated, with controversial findings. Studies in the past two decades have highlighted possible roles of metals, and ionic homeostasis dysregulation has been proposed as the main trigger to motor-neuron degeneration. This study aims at evaluating the possible role of environmental factors in etiopathogenesis of ALS, with a particular attention on metal contamination, focusing on the industrial Briga area in the province of Novara (Piedmont region, North Italy), characterized by: i) a higher incidence of sporadic ALS (sALS) in comparison with the entire province, and ii) the reported environmental pollution. Environmental data from surface, ground and discharge waters, and from soils were collected and specifically analyzed for metal content. Considering the significance of genetic mechanisms in ALS, a characterization for the main ALS genes has been performed to evaluate the genetic contribution for the sALS patients living in the area of study. The main findings of this study are the demonstration that in the Briga area the most common metal contaminants are Cu, Zn, Cr, Ni (widely used in tip-plating processes), that are above law limits in surface waters, discharge waters, and soil. In addition, other metals and metalloids, such as Cd, Pb, Mn, and As show a severe contamination in the same area. Results of genetic analyses show that sALS patients in the Briga area do not carry recurrent mutations or an excess of mutations in the four main ALS causative genes (SOD1, TARDBP, FUS, C9ORF72) and for ATXN2 CAG repeat locus. This study supports the hypothesis that the higher incidence of sALS in Briga area may be related to environmental metal(loid)s contamination, along with other environmental factors. Further studies, implementing analysis of genetic polymorphisms, as well as investigation with long term follow-up, may yield to key aspects into the etiology of ALS. The interplay between different approaches (environmental, chemical, epidemiological, genetic) of our work provides new insights and methodology to the comprehension of the disease etiology.
Subject(s)
Amyotrophic Lateral Sclerosis , Amyotrophic Lateral Sclerosis/etiology , Amyotrophic Lateral Sclerosis/genetics , Causality , Environmental Pollution , Humans , Italy/epidemiology , MutationABSTRACT
Previous meta-analyses have suggested an increased risk of amyotrophic lateral sclerosis (ALS) associated with occupational exposure to extremely low-frequency magnetic fields (ELF-MF). However, results should be interpreted with caution since studies were methodologically heterogeneous. Here, we assessed the feasibility of a pooling study to harmonize and re-analyze available original data. A systematic literature search was conducted. Published epidemiological studies were identified in PubMed and EMF-Portal from literature databases' inception dates until January 2019. The characteristics of all studies were described, including exposure metrics, exposure categories, and confounders. A survey among the principal investigators (PI) was carried out to assess their willingness to provide their original data. The statistical power of a pooling study was evaluated. We identified 15 articles published between 1997 and 2019. Studies differed in terms of outcome, study population, exposure assessment, and exposure metrics. Most studies assessed ELF-MF as average magnetic flux density per working day; however, exposure categories varied widely. The pattern of adjustment for confounders was heterogeneous between studies, with age, sex, and socioeconomic status being most frequent. Eight PI expressed their willingness to provide original data. A relative risk of ≥1.14 for ALS and occupational exposure to ELF-MF can be detected with a power of more than 80% in a pooled study. The pooling of original data is recommended and could contribute to a better understanding of ELF-MF in the etiology of ALS based on a large database and reduced heterogeneity due to a standardized analysis protocol with harmonized exposure metrics and exposure categories. Bioelectromagnetics. © 2021 Bioelectromagnetics Society.