International Journal of Cell Biology rewire the network characterizing the pathological states, by restoring a feedback control via inhibition of c-Abl signaling. Several types of inhibitors have been designed to target with high selectivity the c-Abl kinase by diﬀerent mech- anisms [54, 55]. Allosteric inhibitors repress the catalytic activity by binding to a site far from the kinase-active site. Allosteric binding does not prevent the binding of ATP- competitive inhibitors such as STI571. Experimental data provide evidence that both types of inhibitors can work in synergy to inhibit aberrant activation of Bcr-Abl [55, 56]. Insuﬃcient or excessive inhibitor doses not only may be ineﬃcacious but may also have adverse eﬀects. In addition, targeting of c-Abl to diﬀerent cellular compartments is linked to the catalytic domain conformation. A recent report indicates that binding of STI571 to the catalytic domain can restore the nuclear import of the Bcr-Abl mutant, suggesting that the auto-inhibited conformation of c-Abl is required for nuclear translocation [57]. Interestingly, an allosteric inhibitor, GNF-2, induces a translocation of myristoylated c-Abl to the endoplasmic reticulum, competing with the intramolecular engagement of the NH2-terminal myristate for binding to the c-Abl kinase myristate-binding pocket [58]. A priority is now the identiﬁcation of eﬀective com- bination therapies for native conformations of c-Abl kinases, allowing the reactivation of appropriate regulation circuits in aged neurons. As mentioned, administration of reactive oxygen species scavengers prevents the accumulation of c-Abl and p53 leading to a decreased apoptosis of NPCs. In line with this, treatment with curcumin, an activator of the antioxidant Nfr2 [59] pathway can ameliorate the neurological symptoms and survival of Niemann-Pick type C mice [60]. This suggests the possibility to develop combined targeted therapies of antioxidants in tandem with c-Abl kinase inhibitors [42]. Despite the technical hurdles, rewiring of cell signaling networks via inhibition of a single node, such as c-Abl, may prove an eﬀective therapeutic strategy. Abbreviations c-Abl: Abelson tyrosine kinase ROS: Reactive oxygen species GSH: Glutathione GSSH: Glutathione disulphide SOD: Superoxide dismutases PRxs: Peroxiredoxins GPx: Peroxidases DDR: DNA damage response ATM: Ataxia telangiectasia mutated DNAPKcs: DNA-dependent protein kinase catalytic subunit ATR: Rad-3 related Arg: c-Abl-related gene GVD: Granulovacuolar degeneration AD: Alzheimer disease NTFs: Neuroﬁbrillary tangles Aβ: Amyloid-β ﬁbrils STI571: Imatinib mesylate NPC: Niemann-Pick type C NAC: N-acetylcysteine 5 NPCs: E12.5 cortical neural progenitor cells Cdk5: Cyclin-dependent kinase 5 PKCδ: Protein Kinase C-delta PD: Parkinson’s disease MPTP: 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine MST1: Mammalian Ste20-like kinase1 FOXO3: Forkhead box O3 TTK/PYT/Msp1: (Phosphotyrosine-Picked Threonine Kinase), the human homolog of MSP1 (Monopolar Spindle 1) ER: Endoplasmic reticulum PARP: Poly (ADP-ribose) polymerase Bcr-Abl: Oncogenic fusion protein (breakpoint cluster region). 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