scholarly journals Ataxia Telangiectasia triggers deficits in Reelin pathway

2018 ◽  
Author(s):  
Júlia Canet-Pons ◽  
Ralf Schubert ◽  
Ruth Pia Duecker ◽  
Roland Schrewe ◽  
Sandra Wölke ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ataxia Telangiectasia ◽  
Calcium Binding ◽  
Selective Vulnerability ◽  
Motor Deficits ◽  
Proteomic Profiling ◽  
Extracellular Factor ◽  
Atm Gene ◽  
Excitatory Neurotransmission ◽  
Cerebellar Purkinje Neurons

AbstractAutosomal recessive Ataxia Telangiectasia (A-T) is characterized by radiosensitivity, immunodeficiency and cerebellar neurodegeneration. A-T is caused by inactivating mutations in the Ataxia-Telangiectasia-Mutated (ATM) gene, a serine-threonine protein kinase involved in DNA-damage response and excitatory neurotransmission. The selective vulnerability of cerebellar Purkinje neurons (PN) to A-T is not well understood.Employing global proteomic profiling of cerebrospinal fluid from patients at ages around 15 years we detected reduced Calbindin, Reelin, Cerebellin-1, Cerebellin-3, Protocadherin Fat 2, Sempahorin 7A and increased Apolipoprotein -B, -H, -J peptides. Bioinformatic enrichment was observed for pathways of chemical response, locomotion, calcium binding and complement immunity. This seemed important, since secretion of Reelin from glutamatergic afferent axons is crucial for PN radial migration and spine homeostasis. Reelin expression is downregulated by irradiation and its deficiency is a known cause of ataxia. Validation efforts in 2-month-old Atm-/- mice before onset of motor deficits confirmed transcript reductions for Reelin receptors Apoer2/Vldlr with increases for their ligands Apoe/Apoh and cholesterol 24-hydroxylase Cyp46a1. Concomitant dysregulations were found for Vglut2/Sema7a as climbing fiber markers, glutamate receptors like Grin2b and calcium homeostasis factors (Atp2b2, Calb1, Itpr1), while factors involved in DNA damage, oxidative stress, neuroinflammation and cell adhesion were normal at this stage.These findings show that deficient levels of Reelin signaling factors reflect the neurodegeneration in A-T in a sensitive and specific way. As an extracellular factor, Reelin may be accessible for neuroprotective interventions.

scholarly journals Skeletal Muscle-Restricted Expression of Human SOD1 in Transgenic Mice Causes a Fatal ALS-Like Syndrome

2020 ◽  
Vol 11 ◽  
Author(s):  
Lee J. Martin ◽  
Margaret Wong
Keyword(s):  
Skeletal Muscle ◽  
Dna Damage ◽  
Adipose Tissue ◽  
Satellite Cells ◽  
Selective Vulnerability ◽  
Motor Deficits ◽  
Limb Weakness ◽  
Age Related ◽  
Human Sod1 ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal heterogeneous neurodegenerative disease that causes motor neuron (MN) loss and skeletal muscle paralysis. It is uncertain whether this degeneration of MNs is triggered intrinsically and is autonomous, or if the disease initiating mechanisms are extrinsic to MNs. We hypothesized that skeletal muscle is a primary site of pathogenesis in ALS that triggers MN degeneration. Some inherited forms of ALS are caused by mutations in the superoxide dismutase-1 (SOD1) gene, that encodes an antioxidant protein, so we created transgenic (tg) mice expressing wild-type-, G37R-, and G93A-human SOD1 gene variants only in skeletal muscle. Presence of human SOD1 (hSOD1) protein in skeletal muscle was verified by western blotting, enzyme activity gels, and immunofluorescence in myofibers and satellite cells. These tg mice developed limb weakness and paresis with motor deficits, limb and chest muscle wasting, diaphragm atrophy, and age-related fatal disease with a lifespan shortening of 10–16%. Brown and white adipose tissue also became wasted. Myofibers of tg mice developed crystalline-like inclusions, individualized sarcomere destruction, mitochondriopathy with vesiculation, DNA damage, and activated p53. Satellite cells became apoptotic. The diaphragm developed severe loss of neuromuscular junction presynaptic and postsynaptic integrity, including decreased innervation, loss of synaptophysin, nitration of synaptophysin, and loss of nicotinic acetylcholine receptor and scaffold protein rapsyn. Co-immunoprecipitation identified hSOD1 interaction with rapsyn. Spinal cords of tg mice developed gross atrophy. Spinal MNs formed cytoplasmic and nuclear inclusions, axonopathy, mitochondriopathy, accumulated DNA damage, activated p53 and cleaved caspase-3, and died. Tg mice had a 40–50% loss of MNs. This work shows that hSOD1 in skeletal muscle is a driver of pathogenesis in ALS, that involves myofiber and satellite cell toxicity, and apparent muscle-adipose tissue disease relationships. It also identifies a non-autonomous mechanism for MN degeneration explaining their selective vulnerability as likely a form of target-deprivation retrograde neurodegeneration.

2118-P: Regulation of Ataxia-Telangiectasia and Rad3-Related (ATR)–Dependent DNA Damage Response by Nitric Oxide in ß-Cells

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 2118-P
Author(s):  
CHAY TENG YEO ◽  
BRYNDON OLESON ◽  
JOHN A. CORBETT ◽  
JAMIE K. SCHNUCK
Keyword(s):  
Nitric Oxide ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Damage Response

scholarly journals Exposure of the cytoplasm to low-dose X-rays modifies ataxia telangiectasia mutated-mediated DNA damage responses

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Munetoshi Maeda ◽  
Masanori Tomita ◽  
Mika Maeda ◽  
Hideki Matsumoto ◽  
Noriko Usami ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Ataxia Telangiectasia ◽  
Kinase Inhibitor ◽  
Surrogate Marker ◽  
X Rays ◽  
Ataxia Telangiectasia Mutated ◽  
Whole Cell ◽  
X Ray ◽  
Dna Damage Responses

AbstractWe recently showed that when a low X-ray dose is used, cell death is enhanced in nucleus-irradiated compared with whole-cell-irradiated cells; however, the role of the cytoplasm remains unclear. Here, we show changes in the DNA damage responses with or without X-ray microbeam irradiation of the cytoplasm. Phosphorylated histone H2AX foci, a surrogate marker for DNA double-strand breaks, in V79 and WI-38 cells are not observed in nucleus irradiations at ≤ 2 Gy, whereas they are observed in whole-cell irradiations. Addition of an ataxia telangiectasia mutated (ATM) kinase inhibitor to whole-cell irradiations suppresses foci formation at ≤ 2 Gy. ABL1 and p73 expression is upregulated following nucleus irradiation, suggesting the induction of p73-dependent cell death. Furthermore, CDKN1A (p21) is upregulated following whole-cell irradiation, indicating the induction of cell cycle arrest. These data reveal that cytoplasmic radioresponses modify ATM-mediated DNA damage responses and determine the fate of cells irradiated at low doses.

scholarly journals Enhanced Phosphorylation of Transcription Factor Sp1 in Response to Herpes Simplex Virus Type 1 Infection Is Dependent on the Ataxia Telangiectasia-Mutated Protein

2007 ◽  
Vol 81 (18) ◽  
pp. 9653-9664 ◽  
Author(s):  
Satoko Iwahori ◽  
Noriko Shirata ◽  
Yasushi Kawaguchi ◽  
Sandra K. Weller ◽  
Yoshitaka Sato ◽  
...  
Keyword(s):  
Dna Damage ◽  
Transcription Factor ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Ataxia Telangiectasia ◽  
Ataxia Telangiectasia Mutated ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The ataxia telangiectasia-mutated (ATM) protein, a member of the related phosphatidylinositol 3-like kinase family encoded by a gene responsible for the human genetic disorder ataxia telangiectasia, regulates cellular responses to DNA damage and viral infection. It has been previously reported that herpes simplex virus type 1 (HSV-1) infection induces activation of protein kinase activity of ATM and hyperphosphorylation of transcription factor, Sp1. We show that ATM is intimately involved in Sp1 hyperphosphorylation during HSV-1 infection rather than individual HSV-1-encoded protein kinases. In ATM-deficient cells or cells silenced for ATM expression by short hairpin RNA targeting, hyperphosphorylation of Sp1 was prevented even as HSV-1 infection progressed. Mutational analysis of putative ATM phosphorylation sites on Sp1 and immunoblot analysis with phosphopeptide-specific Sp1 antibodies clarified that at least Ser-56 and Ser-101 residues on Sp1 became phosphorylated upon HSV-1 infection. Serine-to-alanine mutations at both sites on Sp1 considerably abolished hyperphosphorylation of Sp1 upon infection. Although ATM phosphorylated Ser-101 but not Ser-56 on Sp1 in vitro, phosphorylation of Sp1 at both sites was not detected at all upon infection in ATM-deficient cells, suggesting that cellular kinase(s) activated by ATM could be involved in phosphorylation at Ser-56. Upon viral infection, Sp1-dependent transcription in ATM expression-silenced cells was almost the same as that in ATM-intact cells, suggesting that ATM-dependent phosphorylation of Sp1 might hardly affect its transcriptional activity during the HSV-1 infection. ATM-dependent Sp1 phosphorylation appears to be a global response to various DNA damage stress including viral DNA replication.

scholarly journals Association of Ataxia Telangiectasia Mutated (ATM) Gene Mutation/Deletion with Rhabdomyosarcoma

2003 ◽  
Vol 2 (1) ◽  
pp. 88-92 ◽  
Author(s):  
Peilin Zhang ◽  
Kunjan S. Bhakta ◽  
Pier Lorenzo Puri ◽  
Robert Newbury ◽  
James Feramisco ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Ataxia Telangiectasia ◽  
Ataxia Telangiectasia Mutated ◽  
Atm Gene

scholarly journals Tethering DNA Damage Checkpoint Mediator Proteins Topoisomerase IIβ-binding Protein 1 (TopBP1) and Claspin to DNA Activates Ataxia-Telangiectasia Mutated and RAD3-related (ATR) Phosphorylation of Checkpoint Kinase 1 (Chk1)

2011 ◽  
Vol 286 (22) ◽  
pp. 19229-19236 ◽  
Author(s):  
Laura A. Lindsey-Boltz ◽  
Aziz Sancar
Keyword(s):  
Dna Damage ◽  
Ataxia Telangiectasia ◽  
Mammalian Cells ◽  
Binding Protein ◽  
Effector Proteins ◽  
Ataxia Telangiectasia Mutated ◽  
Checkpoint Kinase ◽  
Atr Kinase

The ataxia-telangiectasia mutated and RAD3-related (ATR) kinase initiates DNA damage signaling pathways in human cells after DNA damage such as that induced upon exposure to ultraviolet light by phosphorylating many effector proteins including the checkpoint kinase Chk1. The conventional view of ATR activation involves a universal signal consisting of genomic regions of replication protein A-covered single-stranded DNA. However, there are some indications that the ATR-mediated checkpoint can be activated by other mechanisms. Here, using the well defined Escherichia coli lac repressor/operator system, we have found that directly tethering the ATR activator topoisomerase IIβ-binding protein 1 (TopBP1) to DNA is sufficient to induce ATR phosphorylation of Chk1 in an in vitro system as well as in vivo in mammalian cells. In addition, we find synergistic activation of ATR phosphorylation of Chk1 when the mediator protein Claspin is also tethered to the DNA with TopBP1. Together, these findings indicate that crowding of checkpoint mediator proteins on DNA is sufficient to activate the ATR kinase.

scholarly journals DNA structure-specific priming of ATR activation by DNA-PKcs

2013 ◽  
Vol 202 (3) ◽  
pp. 421-429 ◽  
Author(s):  
Sophie Vidal-Eychenié ◽  
Chantal Décaillet ◽  
Jihane Basbous ◽  
Angelos Constantinou
Keyword(s):  
Dna Damage ◽  
Ataxia Telangiectasia ◽  
Protein A ◽  
Dna Structure ◽  
Specific Response ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Synergistic Activation ◽  
Dependent Protein ◽  
Specific Priming

Three phosphatidylinositol-3-kinase–related protein kinases implement cellular responses to DNA damage. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and ataxia-telangiectasia mutated respond primarily to DNA double-strand breaks (DSBs). Ataxia-telangiectasia and RAD3-related (ATR) signals the accumulation of replication protein A (RPA)–covered single-stranded DNA (ssDNA), which is caused by replication obstacles. Stalled replication intermediates can further degenerate and yield replication-associated DSBs. In this paper, we show that the juxtaposition of a double-stranded DNA end and a short ssDNA gap triggered robust activation of endogenous ATR and Chk1 in human cell-free extracts. This DNA damage signal depended on DNA-PKcs and ATR, which congregated onto gapped linear duplex DNA. DNA-PKcs primed ATR/Chk1 activation through DNA structure-specific phosphorylation of RPA32 and TopBP1. The synergistic activation of DNA-PKcs and ATR suggests that the two kinases combine to mount a prompt and specific response to replication-born DSBs.

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