Persistent DNA damage associated with ATM kinase deficiency promotes microglial dysfunction

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by genome instability and progressive cerebellar neurodegeneration.
• Mutations in the ATM (Ataxia-Telangiectasia Mutated) kinase gene are the primary cause of A-T.
• Microglia, the resident immune cells of the central nervous system, play a critical role in brain homeostasis and disease.

Purpose of the Study:

• To investigate the impact of ATM loss and associated DNA damage on human microglial function.
• To elucidate the molecular mechanisms underlying microglial dysfunction in the context of ATM deficiency.
• To explore the potential contribution of microglial dysfunction to neurodegeneration in Ataxia-telangiectasia.

Main Methods:

• Analysis of DNA damage in ATM-deficient cells.
• Assessment of microglial behavior, including phagocytic activity.
• Investigation of the role of the RELB/p52 non-canonical NF-κB pathway and NIK kinase in microglial dysfunction.
• Examination of cerebellar microglia from individuals with Ataxia-telangiectasia.

Main Results:

• ATM loss and consequent DNA damage induce dysfunctional behavior in human microglia.
• Microglial dysfunction is mediated by the pro-inflammatory RELB/p52 non-canonical NF-κB pathway.
• This pathway activation, driven by persistent DNA damage and NIK kinase, leads to excessive neuronal material clearance.
• Non-canonical NF-κB signaling activation is confirmed in cerebellar microglia of A-T patients.

Conclusions:

• Persistent DNA damage in ATM-deficient microglia activates the RELB/p52 non-canonical NF-κB pathway.
• This aberrant microglial activation contributes to excessive phagocytosis and potentially neurodegeneration in Ataxia-telangiectasia.
• Understanding these mechanisms offers potential therapeutic targets for neurodegenerative diseases associated with ATM deficiency.