Imatinib therapy blocks cerebellar apoptosis and improves neurological symptoms in a mouse model of Niemann‐Pick type C disease

Abstract

Niemann-Pick type C (NPC) disease is a fatal autosomal recessive disorder characterized by the accumulation of free cholesterol and glycosphingolipids in the endosomal-lysosomal system. Patients with NPC disease have markedly progressive neuronal loss, mainly of cerebellar Purkinje neurons. There is strong evidence indicating that cholesterol accumulation and trafficking defects activate apoptosis in NPC brains. The purpose of this study was to analyze the relevance of apoptosis and particularly the proapoptotic c-Abl/p73 system in cerebellar neuron degeneration in NPC disease. We used the NPC1 mouse model to evaluate c-Abl/p73 expression and activation in the cerebellum and the effect of therapy with the c-Abl-specific inhibitor imatinib. The proapoptotic c-Abl/p73 system and the p73 target genes are expressed in the cerebellums of NPC mice. Furthermore, inhibition of c-Abl with imatinib preserved Purkinje neurons and reduced general cell apoptosis in the cerebellum, improved neurological symptoms, and increased the survival of NPC mice. Moreover, this prosurvival effect correlated with reduced mRNA levels of p73 proapoptotic target genes. Our results suggest that the c-Abl/p73 pathway is involved in NPC neurodegeneration and show that treatment with c-Abl inhibitors is useful in delaying progressive neurodegeneration, supporting the use of imatinib for clinical treatment of patients with NPC disease.

c-Abl mediates endothelial apoptosis induced by inhibition of integrins αvβ3 and αvβ5 and by disruption of actin

“…49 On the other hand, a protective effect of STI-571 was seen in vivo in a mouse model of Niemann-Pick type C, where STI-571 increased survival of cerebellar cells by inhibiting c-Abl. 50 In our study, STI-571 protected brain microvascular endothelial cells from the apoptotic effect of RGDfV by suppression of the ability of c-Abl to mediate apoptosis. These findings underscore the potential heterogeneity of imatinib's effects, which may stem from its multiple targets and its different functions in different cells and different settings.…”

Increased Activity and Altered Subcellular Distribution of Lysosomal Enzymes Determine Neuronal Vulnerability in Niemann-Pick Type C1-Deficient Mice

“…[13][14][15]18 At present, the cell death mechanism remains unclear as events related to both apoptosis and autophagy have been identified in Npc1 Ϫ/Ϫ mouse brains. Detection of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive and active caspase-3-immunoreactive Purkinje cells 62,63 is consistent with cell death being due to apoptosis. In keeping with these results, we observed cleaved caspase-3 and Fluoro-Jade C-positive Purkinje cells in the cerebellum but not in the hippocampus of Npc1 Ϫ/Ϫ mice.…”

Cyclodextrin mediates rapid changes in lipid balance in Npc1 mice without carrying cholesterol through the bloodstream

“…44,45 ), this approach is not amenable to NPC disease caused by the loss of NPC1 function ( ‫ف‬ 95% of cases). A limited number of small-molecule therapies have been reported to extend the lifespan of Npc1 Ϫ / Ϫ mice ( 34,35,(46)(47)(48), but none have been shown to extend lifespan more than 10-15% without undesirable side effects. Thus, the initial report ( 5 ) demonstrating that a single injection of HP-␤ -CD extended the lifespan of young and Npc1 Ϫ / Ϫ cells is represented by a double dagger ( ‡ ), and differences in RNA levels resulting from HP-␤ -CD treatment within cells of a given genotype are represented by asterisks (* P < 0.05 to *** P < 0.0005).…”