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

Abstract

Ataxia 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.

Mechanisms of DNA damage‐mediated neurotoxicity in neurodegenerative disease

“…Notably, the development of a new mouse model of AT harboring both ATM nonsense mutation and APTX knockout was found to better recapitulate the neurologic deficits observed in AT (Perez et al , 2021). While progressive cerebellar atrophy and ataxia were not observed in mice with individual mutations in either ATM or APTX, the combination of both mutations lowered the threshold for neuronal genomic instability, resulting in neurological deficits (Perez et al , 2021). This indicates that at least for murine models of AT, the ATM knockout alone is fairly well tolerated, and additional genomic stress is needed to bring about toxicity in neurons (Tal et al , 2018).…”

Daily membrane capacitance changes in mouse neurons

“…It is common practice to report changes in capacitance as a proxy for changes in membrane surface (Haedo and Golowasch 2006; Perez-Garcia et al 2021; Pineda et al 2008; Royeck et al 2008). In juveniles and adults, however, altered capacitance has only being reported for some mouse models of some neurological conditions or after traumatic insult (Adamsky et al ; Akopian et al 2016; Deng et al 2021; Perez et al 2021; Rangel-Barajas et al 2021; Tewari et al 2018). Indeed, after maturation is completed, membrane capacitance is largely considered to be a non-regulated, constant biophysical property of the neurons (however see (Scott et al 2022)), since membrane thickness ( d ) and the properties of membrane lipids, captured by the dielectric constant ( ε ), are also thought to be stable (Gentet et al 2000).…”