PRDX6 Inhibits Neurogenesis through Downregulation of WDFY1-Mediated TLR4 Signal

Abstract

Impaired neurogenesis has been associated with several brain disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). The role of peroxiredoxin 6 (PRDX6) in neurodegenerative diseases is very controversial. To demonstrate the role of PRDX6 in neurogenesis, we compared the neurogenesis ability of PRDX6-overexpressing transgenic (Tg) mice and wild-type mice and studied the involved molecular mechanisms. We showed that the neurogenesis of neural stem cells (NSCs) and the expression of the marker protein were lower in PRDX6 Tg-mice than in wild-type mice. To determine the factors involved in PRDX6-related neural stem cell impairment, we performed a microarray experiment. We showed that the expression of WDFY1 was dramatically decreased in PRDX6-Tg mice. Moreover, WDFY1 siRNA decreases the differentiation ability of primary neural stem cells. Interestingly, WDFY1 reportedly recruits the signaling adaptor TIR-domain-containing adapter-inducing interferon-β (TRIF) to toll-like receptors (TLRs); thus, we showed the relationship among TLRs, PRDX6, and WDFY1. We showed that TLR4 was dramatically reduced in PRDX6 Tg mice, and reduced TLR4 expression and neurogenesis was reversed by the introduction of WDFY1 plasmid in the neural stem cells from PRDX6 Tg mice. This study indicated that PRDX6 inhibits the neurogenesis of neural precursor cells through TLR4-dependent downregulation of WDFY1 and suggested that the inhibitory effect of PRDX6 on neurogenesis play a role in the development of neurodegenerative diseases in the PRDX6 overexpressing transgenic mice.

Genetic and metabolic links between the murine microbiome and memory

“…Examples of known human genes associated with memory also identified in our study include: NTM and KLHl20 that are associated with Alzheimer's disease and DOCK8 and KANK1 that are associated with neurodevelopmental disorders including memory potential [29][30][31]. Examples of known mouse genes associated with memory include Specc1 that was identified in a mouse genetic screen for avoidance learning [32], Prdx6 that was associated with neurogenesis and Alzheimer's disease in mice [33,34] and knock-out mice for Abl2, Nrg3, Shank2, Gria1, and Fgf14 that caused neurodevelopmental defects [35][36][37][38][39]. The other set contains 135 genes not previously associated with memory of which 65 have brain expression [40] (http:// connectivity.brain-map.org/).…”

The Role of Peroxiredoxin 6 in Cell Signaling

“…The impairment of brain neurogenesis is linked to Alzheimer’s (AD) and Parkinson’s disease (PD) [103,104]. Recent work shows that Prdx6 has an inhibitory effect on neurogenesis [105]. In contrast, Prdx6 reduces oxidative stress and counteracts ROS generation, suggesting that Prdx6 plays a neuroprotective role in AD models [103].…”

p39-associated Cdk5 activity regulates dendritic morphogenesis

“…Among them, the transcript level of Wdfy1 was 1.7 fold higher in p39 −/− neurons (Fig. 3 e); of note, Wdfy1 is an adaptor protein in certain signaling pathways and is reported to regulate the differentiation of the neural cell lineage 32 – 34 . Real-time PCR confirmed the increase of Wdfy1 transcript in p39 −/− neurons (4.7-fold increase; Fig.…”