title: Signaling pathway for radiation-induced apoptosis in the lymphoblasts from neuronopathic (type A) and non-neuronopathic (type B) forms of Niemann-Pick disease.
abstract: Deficient activity of human lysosomal hydrolase, acid sphingomyelinase (ASM), results in the neuronopathic (type A) and non-neuronopathic (type B) forms of Niemann-Pick disease (NPD). A deficiency of ASM is known to deprive lymphoblasts of their response to apoptotic induction by X-ray irradiation. To elucidate the genetic heterogeneity of apoptotic induction in NPD cells, we investigated radiation-induced apoptosis of lymphoblasts in patients with type A (genotype: IVS3-2A-G/IVS3-2A-G) and type B (genotype: S436R/S436R) NPD. Epstein-Barr virus (EBV)-transformed lymphoblasts established from a patient with type A NPD, a patient with type B NPD and a normal control were irradiated with 20 Gy and incubated for 24 h. The cells were harvested and the morphological features of apoptosis were observed with DNA-specific fluorochrome bis-benzimide. Exposure of lymphoblasts to 20 Gy of radiation resulted in 25-30% apoptosis of total cells in normal lymphoblasts, 8-9% apoptosis in type A NPD and 20-27% apoptosis in type B NPD. The radiation-induced apoptotic response in the lymphoblasts of type A NPD was significantly different from that of the normal lymphoblasts (P<0.0005). On the other hand, the radiation-induced apoptotic response in type B NPD was not markedly different from that in normal lymphoblasts (P=0.624). In the patient with type B NPD, the signaling pathway for radiation-induced apoptosis was preserved in lymphoblasts, which suggests that the extent of cell signaling system disturbance due to ASM deficiency may be related to the phenotypes in types A and B NPD.
authors.affiliation: Department of Pediatrics, Akita University School of Medicine, Akita 010-8543, Japan.
authors.forename: Tamaki
authors.initials: T
authors.lastname: Mikami
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Takahashi
authors.forename: Akira
authors.initials: A
authors.lastname: Ishida
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Minamiya
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ida
authors.forename: Goro
authors.initials: G
authors.lastname: Takada
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019556:COS Cells; D002461:Cell Line, Transformed; D002675:Child, Preschool; D002746:Chlorpromazine / Q000494:pharmacology; D053938:DNA Fragmentation; D018492:Dopamine Antagonists / Q000494:pharmacology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects*; D008297:Male; D009154:Mutation; D009542:Niemann-Pick Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000528:radiation effects*; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism
chemical_list: D018492:Dopamine Antagonists; D013108:Sphingomyelin Phosphodiesterase; D002746:Chlorpromazine