Saitohin, Which Is Nested in the tau Locus and Confers Allele-specific Susceptibility to Several Neurodegenerative Diseases, Interacts with Peroxiredoxin 6

Abstract

Saitohin is a gene unique to humans and their closest relatives, the function of which is not yet known. Saitohin contains a single polymorphism (Q7R), and its Q and R alleles belong to the H1 and H2 tau haplotype, respectively. The Saitohin Q allele confers susceptibility to several neurodegenerative diseases. To get a handle on Saitohin function, we used it as a bait in a yeast two-hybrid screen. By this assay and subsequent co-immunoprecipitation and glutathione S-transferase pull-down assays, we discovered and confirmed that Saitohin interacts with peroxiredoxin 6, a unique member of that family that is bifunctional and the levels of which increase in Pick disease. The strength of the interaction appeared to be allelespecific, giving the first distinction between the two forms of Saitohin. Saitohin (STH),2 an intronless gene encoding an open reading frame of 128 amino acids, is located in the intron between exons 9 and 10 of the human tau gene (1). It bears no obvious homology to any known protein or motif, and its expression pattern is very similar to that of tau in human tissues. The DNA sequences homologous to the human STH gene reveal an intact, highly conserved open reading frame in the primates most closely related to humans (chimpanzee, bonobo, and gorilla) but not in other primates or in rodents (2, 3). STH provides an evolutionary locus that separates humans and their closest relatives from other mammals.A single nucleotide polymorphism of human STH has been identified that changes glutamine residue 7 to arginine (Q7R (1)). This polymorphism is associated with the two tau gene haplotypes: the Q allele with H1, the R allele with H2 (2, 4). The Q allele is the most common haplotype in humans, but all nonhuman primates are homozygous for the R allele, which makes the Q allele a human-specific marker (2, 3). Hence, the R allele is the ancestral haplotype, whereas the Q allele evolved after the human lineages separated from the other primates.In addition to evolution studies, the R allele of STH was initially found to be associated with Alzheimer disease (1), although subsequent data showing association of the R allele with Alzheimer disease have been inconsistent (2, 4 -10). Recent work may have resolved the conflicting results by indicating that the R allele is associated with Alzheimer disease specifically resulting from the ApoE4 susceptibility factor (11). Furthermore, the Q allele has been shown to be over-represented in several neurodegenerative diseases: progressive supranuclear palsy (12, 13), frontotemporal dementia (4), and Parkinson disease (14). Taken together, these results suggest that identifying a function of STH could implicate several proteins and/or pathway(s) as potential contributors in these neurodegenerative diseases as well.To discover putative functions of STH, we used it as a bait in a yeast two-hybrid screening. We discovered that it interacts with a unique member of the peroxiredoxin family, peroxiredoxin 6 (Prdx6), which has both an antioxidant function and phospholipase act...

Peroxiredoxin 6 interferes with TRAIL-induced death-inducing signaling complex formation by binding to death effector domain caspase

“…Several previous studies have demonstrated that Prx6 has unique binding partners such as surfactant protein A and saitohin. 28,29 Interestingly, only Prx6 uses glutathione as a physiological reductant, while other Prxs use thioredoxin. 16 Then, how does Prx6 regulate TRAIL-mediated cell death through DED caspases?…”

Peroxiredoxin 6: A Bifunctional Enzyme with Glutathione Peroxidase and Phospholipase A2Activities

“…High expression of Prdx6 has been noted in degenerative afflictions of the central nervous system, including Alzheimer's (77), Parkinson's (79), Pick's (42), and CrutzfeldJakob diseases (43), schizophrenia (57), and an experimental mouse model of amyotrophic lateral sclerosis (91). As a potential mechanism for some of these associations, binding of Prdx6 to the protein saitohin may be linked to tau splicing and subsequent neurodegeneration (26). Elevated Prdx6 also occurs in various neoplastic diseases, including malignant mesothelioma (40), bronchogenic squamous cell carcinoma (50), and cancer of the gingivo-buccal area (87), bladder (80), and breast (5).…”

Copy number variations involving the microtubule-associated protein tau in human diseases

“…It is highly expressed in the placenta, muscle, fetal brain and adult brain. In numerous association studies [30][31][32], it has been shown to interact with tau, but also with peroxiredoxin 6 [33], which has antioxidant and phospholipase activity, and with the Abelson kinase [34]. Interestingly, Abelson is widely expressed but is notably highly expressed in hyaline cartilage [35], which could give us a link to the dysmorphic features involving notably the nose in affected patients.…”