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A rare autosomal recessive cerebellar ataxia due to a DNA repair defect characterized by progressive neurological impairment with cerebellar syndrome, oculocutaneous telangiectasia, defects in B and T cell-mediated immunity, and increased susceptibility to malignancies (mainly lymphoid neoplasms). High sensitivity to ionizing radiation limits patient treatments.
Combination of nicotinamide riboside (NAD+ precursor) with CD38 inhibitor (78c) prevents PARP1 hyperactivation-induced NAD+ depletion while maintaining DNA repair capacity through sustained PARP1 availability and enhanced SIRT1/SIRT3 mitochondrial protection
Selective ATR inhibitor (ceralasertib) creates synthetic lethal interaction with ATM deficiency, while intermittent rapamycin-induced autophagy via mTOR/ULK1 pathway clears damaged proteins and organelles during drug holidays to prevent excessive toxicity
Partial CSF1R agonist (PLX5622 derivative) promotes microglial M2 polarization and enhances TREM2/DAP12 signaling to increase microglial phagocytosis of damaged neurons while reducing inflammatory cytokine production (TNF-α, IL-1β) that exacerbates cerebellar degeneration
Rasayana compounds (Withanoside VI, Bacosides) upregulate HSP90 chaperone activity to stabilize mutant ATM kinase folding, while simultaneously activating PGC-1α/NRF1/TFAM pathway for mitochondrial biogenesis to compensate for defective DNA repair-induced cellular stress
Senkyunolide H from Chuanxiong activates RAD51 recombinase filament formation and stability via direct binding to RAD51-C terminus, compensating for defective ATM-mediated DNA double-strand break repair through enhanced HR pathway efficiency
Genetically modified mesenchymal stem cells overexpressing wild-type ATM kinase release ATM-loaded extracellular vesicles that cross blood-brain barrier via LRP1-mediated transcytosis and deliver functional protein to ATM-deficient neurons and glial cells