Cell reports. MedicineSep 17, 2025

Lack of ATM protein causes varied symptoms and movement cell loss in a monkey model of ataxia-telangiectasia

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 3, 2026

Abstract

ATM-deficient rhesus macaques exhibit significant motor impairments and cerebellar atrophy.

These macaques show growth retardation, lymphopenia, and elevated levels of a-fetoprotein.
They display oculocutaneous telangiectasias and heightened sensitivity to ionizing radiation.
Cerebellar atrophy and loss of Purkinje cells are evident, indicating early-stage cerebellar neurodegeneration.
Transcriptomic profiling reveals significant gene expression changes in molecular layer interneurons associated with ATM deficiency.

Simplified

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.

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Lack of ATM protein causes varied symptoms and movement cell loss in a monkey model of ataxia-telangiectasia

Abstract

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