A novel, ataxic mouse model of ataxia telangiectasia caused by a clinically relevant nonsense mutation

eLife

Peter J McKinnon¹  Molly Pind²  Geoffrey G Hicks²  Richard A Gatti³  Kotoka Nakamura³  Harvey Perez⁴  Valentina Sanghez⁴  Jeannie L Kim⁴  May F Abdallah⁴  Callan L Buechsenschuetz⁴  Martin T Egeland⁴  Jose I Chavira⁴  Karen L Vo⁴  Angelina S Norris⁴  Joaquin Madrenas⁵  Paul J Mathews⁶  Michelina Iacovino⁷ 

[1] Center for Pediatric Neurological Disease Research, St. Jude Pediatric Translational Neuroscience Initiative, St. Jude Children’s Research Hospital, Memphis, United States;Department of Biochemistry and Medical Genetics,Max Rady College of Medicine, University of Manitoba, Manitoba, Canada;Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, Los Angeles, United States;The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, United States;The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, United States;Department of Medicine, Harbor-UCLA Medical Center, Torrance, United States;The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, United States;Department of Neurology, Harbor-UCLA Medical Center, Torrance, United States;The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, United States;Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, United States;

关键词: Ataxia Telangiectasia;    cerebellum;    purkinje neurons;    ataxia;    thymus;    cancer;    Mouse;   

DOI  :  10.7554/eLife.64695

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Ataxia Telangiectasia (A-T) and Ataxia with Ocular Apraxia Type 1 (AOA1) are devastating neurological disorders caused by null mutations in the genome stability genes, A-T mutated (ATM) and Aprataxin (APTX), respectively. Our mechanistic understanding and therapeutic repertoire for treating these disorders are severely lacking, in large part due to the failure of prior animal models with similar null mutations to recapitulate the characteristic loss of motor coordination (i.e., ataxia) and associated cerebellar defects. By increasing genotoxic stress through the insertion of null mutations in both the Atm (nonsense) and Aptx (knockout) genes in the same animal, we have generated a novel mouse model that for the first time develops a progressively severe ataxic phenotype associated with atrophy of the cerebellar molecular layer. We find biophysical properties of cerebellar Purkinje neurons (PNs) are significantly perturbed (e.g., reduced membrane capacitance, lower action potential [AP] thresholds, etc.), while properties of synaptic inputs remain largely unchanged. These perturbations significantly alter PN neural activity, including a progressive reduction in spontaneous AP firing frequency that correlates with both cerebellar atrophy and ataxia over the animal’s first year of life. Double mutant mice also exhibit a high predisposition to developing cancer (thymomas) and immune abnormalities (impaired early thymocyte development and T-cell maturation), symptoms characteristic of A-T. Finally, by inserting a clinically relevant nonsense-type null mutation in Atm, we demonstrate that Small Molecule Read-Through (SMRT) compounds can restore ATM production, indicating their potential as a future A-T therapeutic.

【 授权许可】

CC BY