Individual cytokines modulate the neurological symptoms of ATM deficiency in a region specific manner

Abstract

Ataxia-telangiectasia (A-T) is a multi-systemic neurodegenerative disease of childhood caused by the absence of functional ATM (A-T mutated) protein. The cerebellar cortex has the most obvious neuropathology, yet cells in other brain regions are also abnormal. A-T mouse models have been produced that replicate much, though not all, of the complex A-T phenotype. Non-genetic factors, including modulations of the immune status of the animal, have also recently been found to play a role in the disease phenotype. Here we report that these modulations show both cytokine and brain region specificity. The CNS changes induced by broad-spectrum immune challenges such as LPS injections are a complex mixture of neuroprotective (TNFα) and neurodegenerative (IL1β) cytokine responses that change over time. For example, LPS first induces a protective response in A-T neurons through activation of tissue repair genes through infiltration of monocytes with M2 phenotype, followed over time by a set of more degenerative responses. Additional phenotypic complexity arises because the neuronal response to an immune challenge is regionally variable; cerebellum and cortex differ in important ways in their patterns of cellular and biochemical changes. Tracking these changes reveals an important though not exclusive role for the MAP kinase pathway. Our findings suggest brain responses to cytokine challenges are temporally and regionally specific and that both features are altered by the absence of ATM. This implies that management of the immune status of A-T patients might have significant clinical benefit.

Significance: Ataxia-telangiectasia (A-T) causes early cerebellar neurodegeneration, leading to motor inability and early motility in patients. We show that inflammation specifically accelerates A-T neurological symptoms and this effect is modulated by a subset of pro-inflammatory cytokine. Long-term recovery studies demonstrate A-T animals fail to repair the inflammation induced damage. These findings highlight the gene/environment interactions that drive the final set of A-T symptoms and suggest the potential for immunomodulation as a strategy to treat neurodegenerative diseases.