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Journal of Neurology Jun 2024Aberrant DNA methylation alterations are implicated in amyotrophic lateral sclerosis (ALS). Nevertheless, the influence of genetic variants in genes regulating DNA...
BACKGROUND
Aberrant DNA methylation alterations are implicated in amyotrophic lateral sclerosis (ALS). Nevertheless, the influence of genetic variants in genes regulating DNA methylation on ALS patients is not well understood. Therefore, we aim to provide a comprehensive variant profile of genes related to DNA methylation (DNMT1, DNMT3A, DNMT3B, DNMT3L) and demethylation (TET1, TET2, TET3, TDG) and to investigate the association of these variants with ALS.
METHODS
Variants were screened in a cohort of 2240 ALS patients from Southwest China, using controls from the Genome Aggregation Database (n = 9976) and the China Metabolic Analytics Project (n = 10,588). The over-representation of rare variants and their association with ALS risk were evaluated using Fisher's exact test with Bonferroni correction at both allele and gene levels. Kaplan-Meier analysis and Cox regression analysis were employed to explore the relationship between variants and survival.
RESULTS
A total of 210 variants meeting the criteria were identified. Gene-based burden analysis identified a significant increase in ALS risk associated with rare variants in the TET2 gene (OR = 1.95, 95% CI = 1.29-2.88, P = 0.001). Survival analysis demonstrated that patients carrying variants in demethylation-related genes had a higher risk of death compared to those with methylation-related gene variants (HR = 1.29, 95% CI = 1.03-1.86, P = 0.039).
CONCLUSIONS
This study provides a genetic variant profile of genes involved in DNA methylation and demethylation regulation, along with the clinical characteristics of ALS patients carrying these variants. The findings offer genetic evidence implicating disrupted DNA methylation dynamics in ALS.
PubMed: 38907861
DOI: 10.1007/s00415-024-12508-9 -
Nature Aging Jun 2024Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive loss of motor function linked to degenerating extratelencephalic...
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive loss of motor function linked to degenerating extratelencephalic neurons/Betz cells (ETNs). The reasons why these neurons are selectively affected remain unclear. Here, to understand the unique molecular properties that may sensitize ETNs to ALS, we performed RNA sequencing of 79,169 single nuclei from cortices of patients and controls. In both patients and unaffected individuals, we found significantly higher expression of ALS risk genes in THY1 ETNs, regardless of diagnosis. In patients, this was accompanied by the induction of genes involved in protein homeostasis and stress responses that were significantly induced in a wide collection of ETNs. Examination of oligodendroglial and microglial nuclei revealed patient-specific downregulation of myelinating genes in oligodendrocytes and upregulation of an endolysosomal reactive state in microglia. Our findings suggest that selective vulnerability of extratelencephalic neurons is partly connected to their intrinsic molecular properties sensitizing them to genetics and mechanisms of degeneration.
PubMed: 38907103
DOI: 10.1038/s43587-024-00640-0 -
Life Science Alliance Sep 2024Mitochondrial dysfunction is a common feature of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); however, it remains unclear whether this is a cause or...
Mitochondrial dysfunction is a common feature of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); however, it remains unclear whether this is a cause or consequence of the pathogenic process. Analysing multiple aspects of mitochondrial biology across several models of -ALS/FTD, we found morphology, oxidative stress, and mitophagy are commonly affected, which correlated with progressive loss of locomotor performance. Notably, only genetic manipulations that reversed the oxidative stress levels were also able to rescue locomotor deficits, supporting a causative link between mitochondrial dysfunction, oxidative stress, and behavioural phenotypes. Targeting the key antioxidant Keap1/Nrf2 pathway, we found that genetic reduction of or pharmacological inhibition by dimethyl fumarate significantly rescued the -related oxidative stress and motor deficits. Finally, mitochondrial ROS levels were also elevated in patient-derived iNeurons and were effectively suppressed by dimethyl fumarate treatment. These results indicate that mitochondrial oxidative stress is an important mechanistic contributor to pathogenesis, affecting multiple aspects of mitochondrial function and turnover. Targeting the Keap1/Nrf2 signalling pathway to combat oxidative stress represents a therapeutic strategy for -related ALS/FTD.
Topics: Amyotrophic Lateral Sclerosis; Oxidative Stress; NF-E2-Related Factor 2; C9orf72 Protein; Mitochondria; Animals; Disease Models, Animal; Kelch-Like ECH-Associated Protein 1; Humans; Signal Transduction; Frontotemporal Dementia; Phenotype; Drosophila Proteins; Reactive Oxygen Species; Mitophagy; Dimethyl Fumarate; Male
PubMed: 38906677
DOI: 10.26508/lsa.202402853 -
The Medical Letter on Drugs and... Jun 2024
Topics: Humans; Phenylbutyrates
PubMed: 38905535
DOI: 10.58347/tml.2024.1704e -
Medicine Jun 2024Correlations between dietary factors and amyotrophic lateral sclerosis (ALS) have been found in previous observational studies. However, no further studies have used...
Correlations between dietary factors and amyotrophic lateral sclerosis (ALS) have been found in previous observational studies. However, no further studies have used Mendelian randomization to further explore the causal relationship between dietary factors and ALS. Clarifying these relationships is a crucial part of developing nutritional recommendations for ALS prevention. The exposure and outcome datasets employed in this study were extracted from the IEU Open GWAS project (https://gwas.mrcieu.ac.uk/). The exposure datasets involved in our Mendelian analyses consisted of meat intake (processed meat intake, poultry intake, beef intake, pork intake, non-oily fish intake, and oily fish intake), staple foods intake (bread intake and cereal intake), vegetable intake (cooked vegetable intake, salad/raw vegetable intake), fruit intake (fresh fruit intake and dried fruit intake), and beverage intake (coffee intake and tea intake). The weighted median, MR-Egger, Inverse Variance Weighted, Simple mode and Weighted mode methods were all utilized. And we applied Inverse Variance Weighted method as the main judgement criterion for Mendelian randomization analysis. Heterogeneity and pleiotropy analyses were conducted to confirm the validity of the outcomes. Genetically predicted that oily fish intake (OR: 0.7648; 95% CI: 0.5905-0.9904; P = .0420), coffee intake (OR: 0.7385; 95% CI: 0.5660-0.9637; P = .0256), and fresh fruit intake (OR: 0.6165; 95% CI: 0.4007-0.9487; P = .0278) were causally associated with a decreased risk of ALS. Negative results (P > .05) were received for all other dietary factors. This study found that oily fish intake, coffee intake and fresh fruit intake reduced the risk of developing ALS. Additionally, other factors were not associated with ALS.
Topics: Mendelian Randomization Analysis; Amyotrophic Lateral Sclerosis; Humans; Diet; Risk Factors; Fruit; Genome-Wide Association Study; Vegetables; Coffee; Meat
PubMed: 38905382
DOI: 10.1097/MD.0000000000038473 -
Medicine Jun 2024Bulbar dysfunction in amyotrophic lateral sclerosis (ALS) significantly affects daily life, leading to weight loss and reduced survival. Methods for evaluating bulbar... (Observational Study)
Observational Study
Bulbar dysfunction in amyotrophic lateral sclerosis (ALS) significantly affects daily life, leading to weight loss and reduced survival. Methods for evaluating bulbar dysfunction, including videofluoroscopic swallowing studies and the bulbar component of the ALS Functional Rating Scale-Revised (ALSFRS-R), have been employed; however, Korean-specific tools are lacking. The Center for Neurologic Study Bulbar Function Scale (CNS-BFS) comprehensively evaluates bulbar symptoms. This study aimed to develop and validate the Korean version of the CNS-BFS (K-CNS-BFS) to assess bulbar dysfunction in Korean patients with ALS. Twenty-seven patients with ALS were recruited from a tertiary hospital in South Korea based on revised El Escorial criteria. Demographic, clinical, and measurement data were collected. The K-CNS-BFS was evaluated for reliability and validity. Reliability assessment revealed strong internal consistency (Cronbach alpha) for the K-CNS-BFS subscales and total score. Test-retest reliability showed significant correlation. Content validity index was excellent, and convergent validity demonstrated significant correlations between the K-CNS-BFS and relevant measures. Discriminant validity was observed between the K-CNS-BFS and motor/respiratory subscores of the ALSFRS-R. Construct validity demonstrated significant correlations between the K-CNS-BFS subscales and total score. This is the first study to investigate the reliability and validity of the Korean version of the CNS-BFS, which showed consistent and reliable scores that correlated with tests for bulbar or general dysfunction. The K-CNS-BFS effectively measured bulbar dysfunction similar to the original CNS-BFS. The K-CNS-BFS is a reliable and valid tool for assessing bulbar dysfunction in patients with ALS in South Korea.
Topics: Humans; Male; Female; Republic of Korea; Middle Aged; Reproducibility of Results; Amyotrophic Lateral Sclerosis; Aged; Severity of Illness Index; Adult
PubMed: 38905379
DOI: 10.1097/MD.0000000000038216 -
Neurological Sciences : Official... Jun 2024This study aimed at preliminarily assessing, in a cohort of non-demented amyotrophic lateral sclerosis (ALS) patients, the ecological validity, and more specifically the...
BACKGROUND
This study aimed at preliminarily assessing, in a cohort of non-demented amyotrophic lateral sclerosis (ALS) patients, the ecological validity, and more specifically the veridicality, of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and the ALS Cognitive Behavioral Screen (ALS-CBS™), by relating their scores to caregiver-report ratings of cognitive changes.
METHODS
N = 147 patient-caregiver dyads were recruited. Patients were administered the ECAS and ALS-CBS™, whilst caregiver the Caregiver Behavioral Questionnaire (CBQ) and Beaumont Behavioural Inventory (BBI). An Ecological Cognitive Functioning Index (ECFI) was derived from those items of the CBQ and BBI that tap on executive and language changes. Ecological validity was assessed via both correlational and predictive analyses net of caregiver-rated behavioural changes (as assessed by the ECAS-Carer Interview).
RESULTS
The ECFI was associated with the total scores on both the ECAS (p = .014) and ALS-CBS™ (p = .017). When looking at ECAS and ALS-CBS™ subscales, those assessing verbal fluency were selectively associated with the ECFI. The ECFI was higher in patients performing defectively on the ECAS (p = .004) and on the ALS-CBS™ (p = .027).
DISCUSSION
This study suggests that both the ECAS and the ALS-CBS™ represent a valid estimate of non-demented ALS patients' cognitive status in the real world, also highlighting the clinical relevance of cognitive changes reported by caregivers.
PubMed: 38904901
DOI: 10.1007/s10072-024-07660-z -
Frontiers in Neuroscience 2024Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons characterized by muscle weakness, muscle twitching, and muscle wasting.... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons characterized by muscle weakness, muscle twitching, and muscle wasting. ALS is regarded as the third-most frequent neurodegenerative disease, subsequent to Alzheimer's disease (AD) and Parkinson's disease (PD). The World Health Organization (WHO) in 2007 declared that prolonged use of statins may induce development of ALS-like syndrome and may increase ALS risk. Subsequently, different studies have implicated statins in the pathogenesis of ALS. In contrast, results from preclinical and clinical studies highlighted the protective role of statins against ALS neuropathology. Recently, meta-analyses and systematic reviews illustrated no association between long-term use of statins and ALS risk. These findings highlighted controversial points regarding the effects of statins on ALS pathogenesis and risk. The neuroprotective effects of statins against the development and progression of ALS may be mediated by regulating dyslipidemia and inflammatory changes. However, the mechanism for induction of ALS neuropathology by statins may be related to the dysregulation of liver X receptor signaling (LXR) signaling in the motor neurons and reduction of cholesterol, which has a neuroprotective effect against ALS neuropathology. Nevertheless, the exact role of statins on the pathogenesis of ALS was not fully elucidated. Therefore, this narrative review aims to discuss the role of statins in ALS neuropathology.
PubMed: 38903602
DOI: 10.3389/fnins.2024.1422912 -
Frontiers in Psychology 2024Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal, and fast-progressive neurodegenerative disease characterized by the degeneration of motor neurons. ALS...
Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal, and fast-progressive neurodegenerative disease characterized by the degeneration of motor neurons. ALS patients often experience an initial misdiagnosis or a diagnostic delay due to the current unavailability of an efficient biomarker. Since impaired speech is typical in ALS, we hypothesized that functional differences between healthy and ALS participants during speech tasks can be explained by cortical pattern changes, thereby leading to the identification of a neural biomarker for ALS. In this pilot study, we collected magnetoencephalography (MEG) recordings from three early-diagnosed patients with ALS and three healthy controls during imagined (covert) and overt speech tasks. First, we computed sensor correlations, which showed greater correlations for speakers with ALS than healthy controls. Second, we compared the power of the MEG signals in canonical bands between the two groups, which showed greater dissimilarity in the beta band for ALS participants. Third, we assessed differences in functional connectivity, which showed greater beta band connectivity for ALS than healthy controls. Finally, we performed single-trial classification, which resulted in highest performance with beta band features (∼ 98%). These findings were consistent across trials, phrases, and participants for both imagined and overt speech tasks. Our preliminary results indicate that speech-evoked beta oscillations could be a potential neural biomarker for diagnosing ALS. To our knowledge, this is the first demonstration of the detection of ALS from single-trial neural signals.
PubMed: 38903475
DOI: 10.3389/fpsyg.2024.1114811 -
BioRxiv : the Preprint Server For... May 2024Molecular chaperones and co-chaperones are highly conserved cellular components that perform variety of duties related to the proper three-dimensional folding of the...
Molecular chaperones and co-chaperones are highly conserved cellular components that perform variety of duties related to the proper three-dimensional folding of the proteome. The web of factors that carries out this essential task is called the proteostasis network (PN). Ribonucleoproteins (RNPs) represent an underexplored area in terms of the connections they make with the PN. The Survival Motor Neuron (SMN) complex is an RNP assembly chaperone and serves as a paradigm for studying how specific small nuclear (sn)RNAs are identified and paired with their client substrate proteins. SMN protein is the eponymous component of a large complex required for the biogenesis of uridine-rich small nuclear ribonucleoproteins (U-snRNPs) and localizes to distinct membraneless organelles in both the nucleus and cytoplasm of animal cells. SMN forms the oligomeric core of this complex, and missense mutations in its YG box self-interaction domain are known to cause Spinal Muscular Atrophy (SMA). The basic framework for understanding how snRNAs are assembled into U-snRNPs is known, the pathways and mechanisms used by cells to regulate their biogenesis are poorly understood. Given the importance of these processes to normal development as well as neurodegenerative disease, we set out to identify and characterize novel SMN binding partners. Here, we carried out affinity purification mass spectrometry (AP-MS) of SMN using stable fly lines exclusively expressing either wildtype or SMA-causing missense alleles. Bioinformatic analyses of the pulldown data, along with comparisons to proximity labeling studies carried out in human cells, revealed conserved connections to at least two other major chaperone systems including heat shock folding chaperones (HSPs) and histone/nucleosome assembly chaperones. Notably, we found that heat shock cognate protein Hsc70-4 and other HspA family members preferentially interacted with SMA-causing alleles of SMN. Hsc70-4 is particularly interesting because its mRNA is aberrantly sequestered by a mutant form of TDP-43 in mouse and ALS (Amyotrophic Lateral Sclerosis) disease models. Most important, a missense allele of Hsc70-4 (HspA8 in mammals) was recently identified as a bypass suppressor of the SMA phenotype in mice. Collectively, these findings suggest that chaperone-related dysfunction lies at the etiological root of both ALS and SMA.
PubMed: 38903116
DOI: 10.1101/2024.05.15.594402