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Journal of Neurology, Neurosurgery, and... Jun 2024Spinal cord damage is a feature of many spinocerebellar ataxias (SCAs), but well-powered in vivo studies are lacking and links with disease severity and progression...
BACKGROUND
Spinal cord damage is a feature of many spinocerebellar ataxias (SCAs), but well-powered in vivo studies are lacking and links with disease severity and progression remain unclear. Here we characterise cervical spinal cord morphometric abnormalities in SCA1, SCA2, SCA3 and SCA6 using a large multisite MRI dataset.
METHODS
Upper spinal cord (vertebrae C1-C4) cross-sectional area (CSA) and eccentricity (flattening) were assessed using MRI data from nine sites within the ENIGMA-Ataxia consortium, including 364 people with ataxic SCA, 56 individuals with preataxic SCA and 394 nonataxic controls. Correlations and subgroup analyses within the SCA cohorts were undertaken based on disease duration and ataxia severity.
RESULTS
Individuals in the ataxic stage of SCA1, SCA2 and SCA3, relative to non-ataxic controls, had significantly reduced CSA and increased eccentricity at all examined levels. CSA showed large effect sizes (>2.0) and correlated with ataxia severity (r<-0.43) and disease duration (r<-0.21). Eccentricity correlated only with ataxia severity in SCA2 (r=0.28). No significant spinal cord differences were evident in SCA6. In preataxic individuals, CSA was significantly reduced in SCA2 (=1.6) and SCA3 (=1.7), and the SCA2 group also showed increased eccentricity (=1.1) relative to nonataxic controls. Subgroup analyses confirmed that CSA and eccentricity are abnormal in early disease stages in SCA1, SCA2 and SCA3. CSA declined with disease progression in all, whereas eccentricity progressed only in SCA2.
CONCLUSIONS
Spinal cord abnormalities are an early and progressive feature of SCA1, SCA2 and SCA3, but not SCA6, which can be captured using quantitative MRI.
Topics: Humans; Spinocerebellar Ataxias; Male; Female; Middle Aged; Adult; Magnetic Resonance Imaging; Genotype; Aged; Spinal Cord; Cervical Cord; Severity of Illness Index; Case-Control Studies
PubMed: 38383154
DOI: 10.1136/jnnp-2023-332696 -
JCI Insight Feb 2024Radiotherapy induces a type I interferon-mediated (T1IFN-mediated) antitumoral immune response that we hypothesized could be potentiated by a first-in-class ataxia...
Radiotherapy induces a type I interferon-mediated (T1IFN-mediated) antitumoral immune response that we hypothesized could be potentiated by a first-in-class ataxia telangiectasia mutated (ATM) inhibitor, leading to enhanced innate immune signaling, T1IFN expression, and sensitization to immunotherapy in pancreatic cancer. We evaluated the effects of AZD1390 or a structurally related compound, AZD0156, on innate immune signaling and found that both inhibitors enhanced radiation-induced T1IFN expression via the POLIII/RIG-I/MAVS pathway. In immunocompetent syngeneic mouse models of pancreatic cancer, ATM inhibitor enhanced radiation-induced antitumoral immune responses and sensitized tumors to anti-PD-L1, producing immunogenic memory and durable tumor control. Therapeutic responses were associated with increased intratumoral CD8+ T cell frequency and effector function. Tumor control was dependent on CD8+ T cells, as therapeutic efficacy was blunted in CD8+ T cell-depleted mice. Adaptive immune responses to combination therapy provided systemic control of contralateral tumors outside of the radiation field. Taken together, we show that a clinical candidate ATM inhibitor enhances radiation-induced T1IFN, leading to both innate and subsequent adaptive antitumoral immune responses and sensitization of otherwise resistant pancreatic cancer to immunotherapy.
Topics: Animals; Mice; Interferon Type I; Ataxia Telangiectasia; Pancreatic Neoplasms; Immunity; Pyridines; Quinolones
PubMed: 38376927
DOI: 10.1172/jci.insight.168824 -
Journal of Cancer Research and... Oct 2023Colorectal cancer (CRC) is the fifth leading cause of death in India. Until now, the exact pathogenesis concerning CRC signaling pathways is largely unknown; however,...
BACKGROUND
Colorectal cancer (CRC) is the fifth leading cause of death in India. Until now, the exact pathogenesis concerning CRC signaling pathways is largely unknown; however, the diseased condition is believed to deteriorate with lifestyle, aging, and inherited genetic disorders. Hence, the identification of hub genes and therapeutic targets is of great importance for disease monitoring.
OBJECTIVE
Identification of hub genes and targets for identification of candidate hub genes for CRC diagnosis and monitoring.
MATERIALS AND METHODS
The present study applied gene expression analysis by integrating two profile datasets (GSE20916 and GSE33113) from NCBI-GEO database to elucidate the potential key candidate genes and pathways in CRC. Differentially expressed genes (DEGs) between CRC (195 CRC tissues) and healthy control (46 normal mucosal tissue) were sorted using GEO2R tool. Further, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis were performed using Cluster Profiler in Rv. 3.6.1. Moreover, protein-protein interactions (PPI), module detection, and hub gene identification were accomplished and visualized through the Search Tool for the Retrieval of Interacting Genes, Molecular Complex Detection (MCODE) plug-in of Cytoscape v3.8.0. Further hub genes were imported into ToppGene webserver for pathway analysis and prognostic expression analysis was conducted using Gene Expression Profiling Interactive Analysis webserver.
RESULTS
A total of 2221 DEGs, including 1286 up-regulated and 935down-regulated genes mainly enriched in signaling pathways of NOD-like receptor, FoxO, AMPK signalling and leishmaniasis. Three key modules were detected from PPI network using MCODE. Besides, top 20 high prioritized hub genes were selected. Further, prognostic expression analysis revealed ten of the hub genes, namely IL1B, CD44, Glyceraldehyde-3-phosphate dehydrogenase (GAPDH, MMP9, CREB1, STAT1, vascular endothelial growth factor (VEGFA), CDC5 L, Ataxia-telangiectasia mutated (ATM + and CDH1 to be differently expressed in normal and cancer patients.
CONCLUSION
The present study proposed five novel therapeutic targets, i.e., ATM, GAPDH, CREB1, VEGFA, and CDH1 genes that might provide new insights into molecular oncogenesis of CRC.
Topics: Humans; Vascular Endothelial Growth Factor A; Computational Biology; Ataxia Telangiectasia; Cell Movement; Colorectal Neoplasms
PubMed: 38376276
DOI: 10.4103/jcrt.jcrt_620_21 -
Human Brain Mapping Feb 2024Spinocerebellar ataxia type 3 (SCA3) is an inherited movement disorder characterized by a progressive decline in motor coordination. Despite the extensive functional...
Spinocerebellar ataxia type 3 (SCA3) is an inherited movement disorder characterized by a progressive decline in motor coordination. Despite the extensive functional connectivity (FC) alterations reported in previous SCA3 studies in the cerebellum and cerebellar-cerebral pathways, the influence of these FC disturbances on the hierarchical organization of cerebellar functional regions remains unclear. Here, we compared 35 SCA3 patients with 48 age- and sex-matched healthy controls using a combination of voxel-based morphometry and resting-state functional magnetic resonance imaging to investigate whether cerebellar hierarchical organization is altered in SCA3. Utilizing connectome gradients, we identified the gradient axis of cerebellar hierarchical organization, spanning sensorimotor to transmodal (task-unfocused) regions. Compared to healthy controls, SCA3 patients showed a compressed hierarchical organization in the cerebellum at both voxel-level (p < .05, TFCE corrected) and network-level (p < .05, FDR corrected). This pattern was observed in both intra-cerebellar and cerebellar-cerebral gradients. We observed that decreased intra-cerebellar gradient scores in bilateral Crus I/II both negatively correlated with SARA scores (left/right Crus I/II: r = -.48/-.50, p = .04/.04, FDR corrected), while increased cerebellar-cerebral gradients scores in the vermis showed a positive correlation with disease duration (r = .48, p = .04, FDR corrected). Control analyses of cerebellar gray matter atrophy revealed that gradient alterations were associated with cerebellar volume loss. Further FC analysis showed increased functional connectivity in both unimodal and transmodal areas, potentially supporting the disrupted cerebellar functional hierarchy uncovered by the gradients. Our findings provide novel evidence regarding alterations in the cerebellar functional hierarchy in SCA3.
Topics: Humans; Machado-Joseph Disease; Connectome; Magnetic Resonance Imaging; Cerebellum; Cerebellar Cortex
PubMed: 38376240
DOI: 10.1002/hbm.26624 -
Orphanet Journal of Rare Diseases Feb 2024Ataxia telangiectasia (A-T) is an autosomal recessive neurodegenerative disease with widespread systemic manifestations and marked variability in clinical phenotypes. In...
INTRODUCTION
Ataxia telangiectasia (A-T) is an autosomal recessive neurodegenerative disease with widespread systemic manifestations and marked variability in clinical phenotypes. In this study, we sought to determine whether transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) defines subsets of individuals with A-T beyond mild and classic phenotypes, enabling identification of novel features for disease classification and treatment response to therapy.
METHODS
Participants with classic A-T (n = 77), mild A-T (n = 13), and unaffected controls (n = 15) were recruited from two outpatient clinics. PBMCs were isolated and bulk RNAseq was performed. Plasma was also isolated in a subset of individuals. Affected individuals were designated mild or classic based on ATM mutations and clinical and laboratory features.
RESULTS
People with classic A-T were more likely to be younger and IgA deficient and to have higher alpha-fetoprotein levels and lower % forced vital capacity compared to individuals with mild A-T. In classic A-T, the expression of genes required for V(D)J recombination was lower, and the expression of genes required for inflammatory activity was higher. We assigned inflammatory scores to study participants and found that inflammatory scores were highly variable among people with classic A-T and that higher scores were associated with lower ATM mRNA levels. Using a cell type deconvolution approach, we inferred that CD4 + T cells and CD8 + T cells were lower in number in people with classic A-T. Finally, we showed that individuals with classic A-T exhibit higher SERPINE1 (PAI-1) mRNA and plasma protein levels, irrespective of age, and higher FLT4 (VEGFR3) and IL6ST (GP130) plasma protein levels compared with mild A-T and controls.
CONCLUSION
Using a transcriptomic approach, we identified novel features and developed an inflammatory score to identify subsets of individuals with different inflammatory phenotypes in A-T. Findings from this study could be used to help direct treatment and to track treatment response to therapy.
Topics: Humans; Ataxia Telangiectasia; Leukocytes, Mononuclear; Neurodegenerative Diseases; Phenotype; Blood Proteins; RNA, Messenger
PubMed: 38360726
DOI: 10.1186/s13023-024-03073-5 -
Frontiers in Physiology 2024Numerous neurodegenerative diseases result from altered ion channel function and mutations. The intracellular redox status can significantly alter the gating... (Review)
Review
Numerous neurodegenerative diseases result from altered ion channel function and mutations. The intracellular redox status can significantly alter the gating characteristics of ion channels. Abundant neurodegenerative diseases associated with oxidative stress have been documented, including Parkinson's, Alzheimer's, spinocerebellar ataxia, amyotrophic lateral sclerosis, and Huntington's disease. Reactive oxygen and nitrogen species compounds trigger posttranslational alterations that target specific sites within the subunits responsible for channel assembly. These alterations include the adjustment of cysteine residues through redox reactions induced by reactive oxygen species (ROS), nitration, and S-nitrosylation assisted by nitric oxide of tyrosine residues through peroxynitrite. Several ion channels have been directly investigated for their functional responses to oxidizing agents and oxidative stress. This review primarily explores the relationship and potential links between oxidative stress and ion channels in neurodegenerative conditions, such as cerebellar ataxias and Parkinson's disease. The potential correlation between oxidative stress and ion channels could hold promise for developing innovative therapies for common neurodegenerative diseases.
PubMed: 38348223
DOI: 10.3389/fphys.2024.1320086 -
Stem Cell Research Apr 2024The PPP2R2B gene, expressed highly in the brain, harbours trinucleotide CAG repeats in the 5'UTR region, in the range of 7-42 repeats. Individuals carrying CAG repeats...
The PPP2R2B gene, expressed highly in the brain, harbours trinucleotide CAG repeats in the 5'UTR region, in the range of 7-42 repeats. Individuals carrying CAG repeats greater than 43 have been associated to manifest a neurodegenerative disease condition termed as Spinocerebellar Ataxia type 12 (SCA12). An iPSC line from an adult male diagnosed with SCA12 presenting symptoms of gait (Gait Dominance) was generated. It showed pluripotency and trilineage markers without any chromosomal abnormality. This line can be utilized as an essential resource in enhancing our understanding of the molecular pathogenic mechanisms underlying SCA12 by facilitating generation of various neuronal cell types.
Topics: Adult; Humans; Male; Induced Pluripotent Stem Cells; Spinocerebellar Ataxias; Neurons; Trinucleotide Repeats
PubMed: 38340452
DOI: 10.1016/j.scr.2024.103319 -
International Journal of Molecular... Jan 2024An apical component of the cell cycle checkpoint and DNA damage repair response is the ataxia-telangiectasia mutated (ATM) Ser/Thr protein kinase. A variant of ATM,...
An apical component of the cell cycle checkpoint and DNA damage repair response is the ataxia-telangiectasia mutated (ATM) Ser/Thr protein kinase. A variant of ATM, Ser49Cys (rs1800054; minor allele frequency = 0.011), has been associated with an elevated risk of melanoma development; however, the functional consequence of this variant is not defined. ATM-dependent signalling in response to DNA damage has been assessed in a panel of patient-derived lymphoblastoid lines and primary human melanocytic cell strains heterozygous for the ATM Ser49Cys variant allele. The ATM Ser49Cys allele appears functional for acute p53-dependent signalling in response to DNA damage. Expression of the variant allele did reduce the efficacy of oncogene expression in inducing senescence. These findings demonstrate that the Ser49Cys allele has little discernible effect on the acute response to DNA damage but has reduced function observed in the chronic response to oncogene over-expression. Analysis of melanoma, naevus and skin colour genomics and GWAS analyses have demonstrated no association of this variant with any of these outcomes. The modest loss of function detected suggest that the variant may act as a modifier of other variants of ATM/p53-dependent signalling.
Topics: Humans; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; DNA Damage; DNA-Binding Proteins; Melanoma; Oncogenes; Phosphorylation; Protein Serine-Threonine Kinases; Tumor Suppressor Protein p53; Tumor Suppressor Proteins
PubMed: 38338943
DOI: 10.3390/ijms25031664 -
Scientific Reports Feb 2024Machado-Joseph disease (MJD) is a neurodegenerative disorder characterized by widespread neuronal death affecting the cerebellum. Cell therapy can trigger neuronal...
Machado-Joseph disease (MJD) is a neurodegenerative disorder characterized by widespread neuronal death affecting the cerebellum. Cell therapy can trigger neuronal replacement and neuroprotection through bystander effects providing a therapeutic option for neurodegenerative diseases. Here, human control (CNT) and MJD iPSC-derived neuroepithelial stem cells (NESC) were established and tested for their therapeutic potential. Cells' neuroectodermal phenotype was demonstrated. Brain organoids obtained from the Control NESC showed higher mRNA levels of genes related to stem cells' bystander effects, such as BDNF, NEUROD1, and NOTCH1, as compared with organoids produced from MJD NESC, suggesting that Control NESC have a higher therapeutic potential. Graft-derived glia and neurons, such as cells positive for markers of cerebellar neurons, were detected six months after NESC transplantation in mice cerebella. The graft-derived neurons established excitatory and inhibitory synapses in the host cerebella, although CNT neurons exhibited higher excitatory synapse numbers compared with MJD neurons. Cell grafts, mainly CNT NESC, sustained the bystander effects through modulation of inflammatory interleukins (IL1B and IL10), neurotrophic factors (NGF), and neurogenesis-related proteins (Msi1 and NeuroD1), for six months in the mice cerebella. Altogether this study demonstrates the long-lasting therapeutic potential of human iPSC-derived NESC in the cerebellum.
Topics: Mice; Animals; Humans; Induced Pluripotent Stem Cells; Bystander Effect; Neurons; Cerebellum; Machado-Joseph Disease
PubMed: 38332227
DOI: 10.1038/s41598-024-53542-x -
European Journal of Pharmacology Mar 2024At least seven dominantly inherited spinocerebellar ataxias (SCA) are caused by expansions of polyglutamine (polyQ)-encoding CAG repeat. The misfolded and aggregated...
At least seven dominantly inherited spinocerebellar ataxias (SCA) are caused by expansions of polyglutamine (polyQ)-encoding CAG repeat. The misfolded and aggregated polyQ-expanded proteins increase reactive oxygen species (ROS), cellular toxicity, and neuroinflammation in the disease pathogenesis. In this study, we evaluated the anti-inflammatory potentials of coumarin derivatives LM-021, LMDS-1, LMDS-2, and pharmacological chaperone tafamidis using mouse BV-2 microglia and SCA3 ataxin-3 (ATXN3)/Q-GFP SH-SY5Y cells. The four tested compounds displayed anti-inflammatory activity by suppressing nitric oxide (NO), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α production, and CD68 antigen (CD68) and histocompatibility-2 (MHCII) expression in lipopolysaccharides (LPS)/interferon (IFN)-γ-stimulated BV-2 microglia. In retinoic acid-differentiated ATXN3/Q-GFP-expressing SH-SY5Y cells inflamed with LPS/IFN-γ-primed BV-2 conditioned medium, treatment with test compounds mitigated the increased caspase 1 activity and lactate dehydrogenase release, reduced ROS and ATXN3/Q aggregation, and promoted neurite outgrowth. Examination of IL-1β and IL-6-mediated signaling pathways revealed that LM-021, LMDS-1, LMDS-2, and tafamidis decreased NLR family pyrin domain containing 1 (NLRP1), c-Jun N-terminal kinase/c-Jun proto-oncogene (JNK/JUN), inhibitor of kappa B (IκBα)/P65, mitogen-activated protein kinase 14/signal transducer and activator of transcription 1 (P38/STAT1), and/or Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling. The study results suggest the potential of LM-021, LMDS-1, LMDS-2, and tafamidis in treating SCA3 and probable other polyQ diseases.
Topics: Animals; Humans; Mice; Anti-Inflammatory Agents; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Machado-Joseph Disease; Neuroblastoma; NF-kappa B; Reactive Oxygen Species; Signal Transduction
PubMed: 38320719
DOI: 10.1016/j.ejphar.2024.176370