ATM deficiency drives phenotypic diversity and Purkinje cell degeneration in a macaque model of ataxia-telangiectasia

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Ataxia-telangiectasia (A-T) is a hereditary neurodegenerative disorder caused by mutations in the ATM (ataxia-telangiectasia mutated) gene. Although existing rodent models reproduce some of the multi-systemic features of A-T, they notably fail to recapitulate the severe neurological manifestations, particularly the profound cerebellar atrophy and associated ataxia. To address this limitation, we have generated ATM-deficient rhesus macaques using CRISPR-Cas9. These macaques exhibit hallmark features of A-T, including growth retardation, lymphopenia, elevated a-fetoprotein levels, oculocutaneous telangiectasias, heightened sensitivity to ionizing radiation, and most critically, cerebellar atrophy, Purkinje cell loss, and early-stage cerebellar neurodegeneration leading to significant motor impairments. Single-nucleus transcriptomic profiling of the cerebellum revealed pronounced gene expression changes associated with ATM deficiency, particularly in molecular layer interneurons (MLIs), which are implicated in Purkinje cell loss. This non-human primate model provides deeper insights into the pathogenesis of A-T and represents a promising and valuable platform for developing therapeutic strategies. • CRISPR-Cas9-generated ATM deficiency in macaque models human A-T • ATM-deficient macaques faithfully recapitulate key phenotypes of human A-T • Progressive cerebellar atrophy with early onset is observed in ATM-deficient macaques • ATM deficiency causes Purkinje cell loss and transcriptomic shifts in cerebellar cell types Xu et al. report that CRISPR-Cas9-engineered ATM-deficient rhesus macaques model key features of ataxia-telangiectasia, including growth retardation, immune deficiency, and most critically, early-onset cerebellar atrophy. This model provides deeper insights into the pathogenesis of A-T and represents a promising and valuable platform for developing therapeutic strategies.