Defective signal transduction in B lymphocytes lacking presenilin proteins

Abstract

The mammalian presenilin (PS) proteins mediate the posttranslational cleavage of several protein substrates, including amyloid precursor protein, Notch family members, and CD44, but they have also been suggested to function in diverse cellular processes, including calcium-dependent signaling and apoptosis. We carried out an integrative computational study of multiple genomic datasets, including RNA expression, protein interaction, and pathway analyses, which implicated PS proteins in Toll

Presenilin-dependent regulated intramembrane proteolysis and γ-secretase activity

“…A strong association between presenilins and the immune system has been reported from phenotypic characterization of several in vivo models of presenilin biology and identification of g-secretase substrates. The phenotype of PS1 +/-PS2 -/-partial deficient mice revealed a novel in vivo function for presenilins in the immune system [19], which has been substantiated in T cell and B cellspecific presenilin-deficient animals [25,26]. The PS1 +/-PS2 -/-animals are relatively normal up to about 6 months of age, after which the majority of the mice develop a systemic lupus erythematosus (SLE)-like autoimmune disease [19].…”

“…The PS1 +/-PS2 -/-animals are relatively normal up to about 6 months of age, after which the majority of the mice develop a systemic lupus erythematosus (SLE)-like autoimmune disease [19]. Ablation of presenilin in T cells results in inefficient generation of CD4+ T cells, a phenotype that correlates with evidence of impaired T cell receptor (TCR) signalling [25], while selective loss of presenilins in B cells compromises responsiveness to LPS and B cell antigen receptor-induced proliferation and signal transduction events [26]. Likewise, abnormal vasculogenesis and angiogenesis have been reported in PS1 and Aph-1a deficient mice [68,141].…”

“…The phenotype of PS1 +/-PS2 -/-partial deficient mice is normal up to approximately six months, when the majority of the mice develop skin lesions similar to seborrheic keratosis, the common benign wart seen frequently in elderly humans, and an autoimmune disease characterized by dermatitis, glomerulonephritis, keratitis and vasculitis, as seen in human systemic lupus erythematosus [19]. Subsequent studies have also employed the Cre/LoxP system to more closely study the long-term role of PS1 in lymphoid T cells [25] and B cells [26]. Deficiency in both PS1 and PS2 functions antagonise T cell homeostasis and signalling [25], while B cells deficient in PS1 and PS2 present a deficit in both lipopolysaccharide (LPS) and B-cell antigen receptorinduced proliferation and signal transduction events [26].…”

“…Subsequent studies have also employed the Cre/LoxP system to more closely study the long-term role of PS1 in lymphoid T cells [25] and B cells [26]. Deficiency in both PS1 and PS2 functions antagonise T cell homeostasis and signalling [25], while B cells deficient in PS1 and PS2 present a deficit in both lipopolysaccharide (LPS) and B-cell antigen receptorinduced proliferation and signal transduction events [26]. From these studies it has been concluded that in addition to the central nervous system, the skin [20,27] and the immune system appear to be especially sensitive to a partial loss of presenilin functions [19,28].…”

Genetics of Alzheimer's Disease: An Insight Into Presenilins and Apolipoprotein E Instigated Neurodegeneration

“…In addition, they play a vital role in B cell function. B cells lacking both PS1 and PS2 function have an unanticipated and significant dearth in both lipopolysaccharide and B cell antigen receptor-induced proliferation and signal transduction events, including an impaired anti-IgM-mediated calcium flux (Yagi et al, 2008). Despite the production of diverse lengths of Aβ by gamma-secretase through an undisclosed mechanism, only Aβ 42 has been estimated to participate in AD pathology (Wanngren et al, 2010).…”