scholarly journals Reducing Mitochondrial ROS Improves Disease-related Pathology in a Mouse Model of Ataxia-telangiectasia

2013 ◽  
Vol 21 (1) ◽  
pp. 42-48 ◽  
Author(s):  
Anthony D D'Souza ◽  
Ian A Parish ◽  
Diane S Krause ◽  
Susan M Kaech ◽  
Gerald S Shadel
Keyword(s):  
Mouse Model ◽  
Ataxia Telangiectasia ◽  
Mitochondrial Ros

scholarly journals Atrophy, oxidative switching and ultrastructural defects in skeletal muscle of the ataxia telangiectasia mouse model

2019 ◽  
Vol 132 (5) ◽  
pp. jcs223008 ◽  
Author(s):  
Valentina Tassinari ◽  
Vincenzo De Gennaro ◽  
Gina La Sala ◽  
Daniela Marazziti ◽  
Giulia Bolasco ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mouse Model ◽  
Ataxia Telangiectasia

scholarly journals A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

2011 ◽  
Vol 179 (3) ◽  
pp. 1533-1541 ◽  
Author(s):  
Dorit Raz-Prag ◽  
Ronit Galron ◽  
Niva Segev-Amzaleg ◽  
Arieh S. Solomon ◽  
Yosef Shiloh ◽  
...  
Keyword(s):  
Mouse Model ◽  
Ataxia Telangiectasia ◽  
Retinal Pathology

scholarly journals A novel, ataxic mouse model of Ataxia Telangiectasia caused by a clinically relevant nonsense mutation

2020 ◽  
Author(s):  
Harvey Perez ◽  
May F. Abdallah ◽  
Jose I. Chavira ◽  
Martin T. Egeland ◽  
Karen L. Vo ◽  
...  
Keyword(s):  
Mouse Model ◽  
Ataxia Telangiectasia ◽  
Nonsense Mutation ◽  
Genome Stability ◽  
Cerebellar Atrophy ◽  
Genotoxic Stress ◽  
Purkinje Neuron ◽  
Cerebellar Dysfunction ◽  
Severe Ataxia ◽  
Human Disorder

AbstractAtaxia Telangiectasia (A-T) is caused by null mutations in the genome stability gene, ATM (A-T mutated). In mice, similar null mutations do not replicate A-T’s characteristic severe ataxia with associated cerebellar dysfunction and atrophy. By increasing genotoxic stress, through the insertion of null mutations in the Atm (nonsense) and related Aptx (knockout) genes, we have generated a novel A-T mouse that first develops mild ataxia, associated with abnormal Purkinje neuron (PN) activity and decreased size, progressing to severe ataxia correlated with further reduced PN activity as well as PN loss and overall cerebellar atrophy. These mice also exhibit high incidences of cancer and immune abnormalities that are all hallmarks of the human disorder. Enabled by the insertion of a clinically relevant nonsense mutation in Atm, we demonstrate that small molecule readthrough (SMRT) compounds can restore ATM production, indicating their potential as a future A-T therapeutic.

scholarly journals FXR1 is a novel MRE11-binding partner and participates in oxidative stress responses

2020 ◽  
Vol 61 (3) ◽  
pp. 368-375 ◽  
Author(s):  
Fei Qi ◽  
Qingmei Meng ◽  
Ikue Hayashi ◽  
Junya Kobayashi
Keyword(s):  
Oxidative Stress ◽  
Stress Responses ◽  
Ataxia Telangiectasia ◽  
Strand Break ◽  
Independent Manner ◽  
Binding Partner ◽  
Mitochondrial Ros ◽  
Dna Double Strand Break ◽  
Progressive Cerebellar Ataxia ◽  
Oxidative Stress Responses

Abstract Ataxia-telangiectasia (AT) and MRE11-defective Ataxia-telangiectasia-like disorder (ATLD) patients show progressive cerebellar ataxia. ATM, mutated in AT, can be activated in response to oxidative stress as well as DNA damage, which could be linked to disease-related neurodegeneration. However, the role of MRE11 in oxidative stress responses has been elusive. Here, we showed that MRE11 could participate in ATM activation during oxidative stress in an NBS1/RAD50-independent manner. Importantly, MRE11 was indispensable for ATM activation. We identified FXR1 as a novel MRE11-binding partner by mass spectrometry. We confirmed that FXR1 could bind with MRE11 and showed that both localize to the cytoplasm. Notably, MRE11 and FXR1 partly localize to the mitochondria, which are the major source of cytoplasmic reactive oxygen species (ROS). The contribution of FXR1 to DNA double-strand break damage responses seemed minor and limited to HR repair, considering that depletion of FXR1 perturbed chromatin association of homologous recombination repair factors and sensitized cells to camptothecin. During oxidative stress, depletion of FXR1 by siRNA reduced oxidative stress responses and increased the sensitivity to pyocyanin, a mitochondrial ROS inducer. Collectively, our findings suggest that MRE11 and FXR1 might contribute to cellular defense against mitochondrial ROS as a cytoplasmic complex.

Impaired insulin secretion in a mouse model of ataxia telangiectasia

2007 ◽  
Vol 293 (1) ◽  
pp. E70-E74 ◽  
Author(s):  
Philip D. Miles ◽  
Kai Treuner ◽  
Marc Latronica ◽  
Jerrold M. Olefsky ◽  
Carrolee Barlow
Keyword(s):  
Insulin Secretion ◽  
Mouse Model ◽  
Ataxia Telangiectasia ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Oral Glucose ◽  
Pronounced Increase ◽  
Glucose Levels ◽  
Impaired Insulin Secretion ◽  
Impaired Insulin

Ataxia telangiectasia (A-T) is an autosomal recessive disease caused by mutations in the A-T mutated (ATM) gene. The gene encodes a serine/threonine kinase with important roles in the cellular response to DNA damage, including the activation of cell cycle checkpoints and induction of apoptosis. Although these functions might explain the cancer predisposition of A-T patients, the molecular mechanisms leading to glucose intolerance and diabetes mellitus (DM) are unknown. We have investigated the pathogenesis of DM in a mouse model of A-T. Here we show that young Atm-deficient mice show normal fasting glucose levels and normal insulin sensitivity. However, oral glucose tolerance testing revealed delayed insulin secretion and resulting transient hyperglycemia. Aged Atm−/− mice show a pronounced increase in blood glucose levels and a decrease in insulin and C-peptide levels. Our findings support a role for ATM in metabolic function and point toward impaired insulin secretion as the primary cause of DM in A-T.

scholarly journals Oxidative stress-driven pulmonary inflammation and fibrosis in a mouse model of human ataxia-telangiectasia

Redox Biology ◽  
2018 ◽  
Vol 14 ◽  
pp. 645-655 ◽  
Author(s):  
Ruth Duecker ◽  
Patrick Baer ◽  
Olaf Eickmeier ◽  
Maja Strecker ◽  
Jennifer Kurz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mouse Model ◽  
Ataxia Telangiectasia ◽  
Pulmonary Inflammation
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