Abstract
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.
Highlights
Ataxia Telangiectasia (A-T) is a rare (1 in ~100,000) (Swift et al 1986), autosomal recessive genetic disorder characterized by cancer predisposition, immune deficiency, and a highly penetrant progressive and severe ataxia linked to cerebellar atrophy (Rothblum-Oviatt et al 2016; Boder and Sedgwick 1958; Levy and Lang 2018)
In the AtmR35X/R35X; Aptx-/- mice, we found the gross size of the cerebellum to be normal early in life, but 321 significant atrophy developed as the severity of ataxia increased (Fig. 5A)
The presence of ataxia and cerebellar atrophy in this new mouse model is of great significance, as it provides for the very first time a resource to elucidate the mechanisms of neurological dysfunction, and a critically needed in vivo model to test severely needed A-T therapeutics, such as the read-through compounds we describe here
Summary
Ataxia Telangiectasia (A-T) is a rare (1 in ~100,000) (Swift et al 1986), autosomal recessive genetic disorder characterized by cancer predisposition, immune deficiency, and a highly penetrant progressive and severe ataxia linked to cerebellar atrophy (Rothblum-Oviatt et al 2016; Boder and Sedgwick 1958; Levy and Lang 2018). Its roles are still emerging, ATM has been implicated in oxidative stress homeostasis (Guo et al 2010) and mitophagy (Valentin-Vega and Kastan 2012; Pizzamiglio, Focchi, and Antonucci 2020) It is unclear why ATM deficiency causes ataxia, but it is far from the only DDR protein linked to ataxia, 67 as Aprataxin (APTX) (Aicardi et al 1988), Meiotic recombination 11 homolog 1 (MRE11) (Sedghi et al 68 2018), Nibrin (NBS1) (van der Burgt et al 1996), Senataxin (SETX) (Moreira et al 2004), and Tyrosyl DNA Phosphodiesterase 1 (TDP1) (Takashima et al 2002) when absent or dysfunctional can cause cerebellar-related ataxia. We report proof-of-principle experiments demonstrating that clinically relevant genetic mutations incorporated into the A-T mouse model are amenable to read-through compounds and appropriate for preclinical testing of SMRT compounds
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