Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive neurodegeneration and cerebellar ataxia. A-T is causally linked to defects in ATM, a master regulator of the response to and repair of DNA double-strand breaks. The molecular basis of cerebellar atrophy and neurodegeneration in A-T patients is unclear. Here we report and examine the significance of increased PARylation, low NAD+, and mitochondrial dysfunction in ATM-deficient neurons, mice, and worms. Treatments that replenish intracellular NAD+ reduce the severity of A-T neuropathology, normalize neuromuscular function, delay memory loss, and extend lifespan in both animal models. Mechanistically, treatments that increase intracellular NAD+ also stimulate neuronal DNA repair and improve mitochondrial quality via mitophagy. This work links two major theories on aging, DNA damage accumulation, and mitochondrial dysfunction through nuclear DNA damage-induced nuclear-mitochondrial signaling, and demonstrates that they are important pathophysiological determinants in premature aging of A-T, pointing to therapeutic interventions.
Illumina Genome Analyzer II paired end sequencing; Illumina sequencing of C. elegans dauer entry daf-2(el370) sample 2 DauerEntryDAF2-2 polyA+ RNAseq random fragment library RW0001
Illumina Genome Analyzer II paired end sequencing; Illumina sequencing of C. elegans dauer exit daf-2(el370) sample 2 DauerExitDAF2-2 polyA+ RNAseq random fragment library RW0001
Illumina Genome Analyzer II paired end sequencing; Illumina sequencing of C. elegans dauer daf-2(el370) sample 2 DauerDAF2-2 polyA+ 76bp SE RNAseq random fragment library RW0001
Illumina HiSeq 2000 paired end sequencing; Illumina sequencing of C. elegans dauer daf-2(el370) sample 2-1 DauerDAF2-2-1 polyA+ 100bp PE RNAseq random fragment library RW0001