Early onset neurodegeneration is a hallmark of Ataxia telangiectasia (A-T), Ataxia-telangiectasia like disease (A-TLD) and Nijmegen breakage syndrome (NBS), three inherited disorders caused by genetic defects in ATM, Mre11 and Nbs1 proteins. These functionally interdependent proteins mediate  the response to and repair of DNA double-strand breaks (DSBs). The neurological manifestation in A-T and A-TLD differ from NBS, the former presenting progressive cerebellar ataxia, the latter microcephaly and mental retardation. The mechanisms underlying neurodegeneration in these syndromes are unclear, but accumulation of DNA damage, oxidative stress and mitochondrial dysfunction, have been variably implicated. Using proliferating ihNSCs, we have demonstrated that ATM knockdown markedly delays repair of DNA DSBs, reduces the accumulation of HIF-1a and CAIX, both during proliferation and terminal differentiation under hypoxia, reduces the yield of GABAergic neurons and oligodendrocytes. Moreover, ATM-deficient oligodendrocytes are vulnerable to oxidative stress conditions. Taking advantage of the iPSC technology, we have reprogrammed fibroblasts from A-T patients and normal donors, and established from these proliferating neural precursor cells (NPCs) that can differentiate into neurons  (>90% b-Tubulin III+/Map2+). AT derived post-mitotic neurons are remarkably dysfunctional in the response to DNA damage,  and although exhibit normal electrophysiological activities display deficits in the expression of SYP and PSD95 as well as of SCG10 and KChIP. Most importantly, AT neurons exhibit high levels of DNA-Top1 covalent complexes, lilely to impair in the long term global transcription and neuronal survival.  These studies are providing fundamental insights into the mechanisms of neurodegeneration arising from dysfunctional DNA damage response/repair, and advanced in vitro model systems that can be employed in cell based assays to screen for candidate therapeutics.