Disease relevance of Pdcd6

• In contrast to PS1(-/-) mice, PS2(-/-) mice are viable and fertile and develop only mild pulmonary fibrosis and hemorrhage with age [1].
• Mice heterozygous for PS1 and homozygous for PS2 (PS1(+/)(-)PS2(-)(/)(-)) developed splenomegaly with severe granulocyte infiltration [2].
• Therapeutic actions of insulin-like growth factor I on APP/PS2 mice with severe brain amyloidosis [3].
• We have studied the cleavage of PS1 and PS2 in transiently and stably transfected hamster kidney and mouse and human neuroblastoma cells by immunoblot and pulse-chase experiments [4].
• Nonetheless, these results collectively suggest that the novel PS-2 alleles described here, especially R71W, affect PS-2 function and may potentially confer a moderate risk of susceptibility to breast cancer [5].

Psychiatry related information on Pdcd6

• ALG-3, a truncated form of the familial Alzheimer's disease gene PS2, confers resistance to TCR- and Fas-induced apoptosis [6].

High impact information on Pdcd6

• Deficient Ca(2+) signaling in DKO MEFs can be rescued by expression of wild-type PS1 or PS2 but not by expression of PS1-M146V or PS2-N141I mutants [7].
• This observation indicates that PS1 (and PS2) may contain the active site of gamma-secretase [8].
• We conclude that the presenilins play a widespread role in embryogenesis, that there is a functional redundancy between PS1 and PS2, and that both vertebrate presenilins, like their invertebrate homologs, are essential for Notch signaling [9].
• The majority of early-onset cases of familial Alzheimer's disease (FAD) are linked to mutations in two related genes, PS1 and PS2, located on chromosome 14 and 1, respectively [10].
• Mutations in the presenilin genes (PS1, PS2), the leading cause of autosomal dominant familial Alzheimer's disease (FAD), cause highly specific alterations in intracellular calcium signaling pathways that may contribute to the neurodegenerative and pathological lesions of the disease [11].

Chemical compound and disease context of Pdcd6

• Hence, cooperative interactions of NH2- and COOH-terminal fragments generated from full-length mutant PS2 may be important for the overproduction of Abeta42 that may underlie familial Alzheimer's disease [12].
• In this study, we tested the hypothesis that neutralizing antibody for integrin alpha4 (PS2) may reduce bleomycin (BL)-induced lung fibrosis in vivo [13].

Biological context of Pdcd6

• Our results indicate that mutant PS2 inhibits normal neuronal cell differentiation and that RyR-mediated calcium overrelease may be a significant factor [14].
• In double mutant amyloid precursor protein/presenilin 2 (APP/PS2) mice, a transgenic model of AD, vessel homeostasis is disturbed [15].
• Thus, the PS2 gene is required for some forms of cell death in diverse cell types, and its function is opposed by ALG-3 [16].
• These data indicate that: (i) the Abeta42-promoting effects of mutant PS2 proteins reach the maximum level with a given single amino acid substitution (i.e. N141I or M239V); and (ii) the expression of full-length mutant PS2 is required for the overproduction of Abeta42 [12].
• The rat PS-2 cDNA encoded 448 amino acids, and the deduced amino acid sequence was highly homologous to those of the human (94.9%), mouse (96.4%) and Xenopus (70.8%) [17].

Anatomical context of Pdcd6

• To explore the physiologic function of ALG-2 in T-cell development and function, we generated mice harboring a null mutation in the alg-2 gene [18].
• PS1- and PS2-mediated activities were individually characterized using blastocyst-derived (BD) cells and membranes from PS1+/--PS2-/- and PS1-/-PS2+/+ mice, respectively [19].
• We investigated the impact of PS/gamma-secretase on mitochondrial function using mouse embryonal fibroblasts derived from wild-type, PS1-/-, PS2-/- and PS double knock-out (PSKO) embryos [20].
• PS2-/- cells showed a significantly lower basal respiratory rate as compared to other cell lines [20].
• Interestingly, pre-treatment of isolated mitochondria with the gamma-secretase inhibitor L-685,458 resulted in a decreased population of mitochondria with high DeltaPsim in PSwt and PS1-/- cells, indicating that PS2/gamma-secretase activity can modify DeltaPsim [20].

Associations of Pdcd6 with chemical compounds

• Moreover, dantrolene, a blocker of RyR reduced the PS2 mutation-induced interference of cell differentiation and calcium release, but caffeine, an activator of RyR, exacerbated PS2 mutation-induced interference with cell differentiation [14].
• ALG-3 and antisense PS2 protect PC12 cells from glutamate-induced apoptosis but not from death induced by hydrogen peroxide or the free radical MPP+ [16].
• Here, we report that PS1/PS2 null and dominant negative PS1 mutants, which are mutated at aspartate residue 257 or 385, did not affect signaling of the UPR [21].
• Our results showed that overexpression of either wild type or mutant PS2 in these cell lines did not directly induce apoptosis or increase the susceptibility to apoptosis induced by staurosporine or H(2)O(2) [22].
• To study PS2 expression during differentiation, mouse embryonic carcinoma P19 cells were treated with retinoic acid [23].

Analytical, diagnostic and therapeutic context of Pdcd6

• Molecular dissection of domains in mutant presenilin 2 that mediate overproduction of amyloidogenic forms of amyloid beta peptides. Inability of truncated forms of PS2 with familial Alzheimer's disease mutation to increase secretion of Abeta42 [12].
• By Western blot analysis, APP and PS2-like immunoreactivity were visualized as a 100-130 and 52 kDa bands, respectively [24].
• Semi-quantitative PCR of reverse-transcribed RNA (RT-PCR) analysis revealed that PS1 and PS2 mRNA are expressed ubiquitously and at comparable levels in most human and mouse tissues, including adult brain [25].
• In situ hybridization analysis in adult mouse brain revealed that PS1 and PS2 mRNAs are enriched in neurons of the hippocampal formation and entorhinal cortex [25].
• Immunofluorescent staining detected by confocal microscopy suggested that both native PS1 and PS2 are localized mainly in the Golgi/ER apparatus [26].

References