The metabolic signaling of the nucleoredoxin-like 2 gene supports brain function

Abstract

The nucleoredoxin gene NXNL2 encodes for two products through alternative splicing, rod-derived cone viability factor-2 (RdCVF2) that mediates neuronal survival and the thioredoxin-related protein (RdCVF2L), an enzyme that regulates the phosphorylation of TAU. To investigate the link between NXNL2 and tauopathies, we studied the Nxnl2 knockout mouse ( Nxnl2 −/− ). We established the expression pattern of the Nxnl2 gene in the brain using a Nxnl2 reporter mouse line, and characterized the behavior of the Nxnl2 −/− mouse at 2 months of age. Additionally, long term potential recording and metabolomic from hippocampal specimens were collected at 2 months of age. We studied TAU oligomerization, phosphorylation and aggregation in Nxnl2 −/− brain at 18 months of age. Finally, newborn Nxnl2 −/− mice were treated with adeno-associated viral vectors encoding for RdCVF2, RdCVF2L or both and measured the effect of this therapy on long-term potential, glucose metabolism and late-onset tauopathy. Nxnl2 −/− mice at 2 months of age showed severe behavioral deficiency in fear, pain sensitivity, coordination, learning and memory. The Nxnl2 −/− also showed deficits in long-term potentiation, demonstrating that the Nxnl2 gene is involved in regulating brain functions. Dual delivery of RdCVF2 and RdCVF2L in newborn Nxnl2 −/− mice fully correct long-term potentiation through their synergistic action. The expression pattern of the Nxnl2 gene in the brain shows a predominant expression in circumventricular organs, such as the area postrema . Glucose metabolism of the hippocampus of Nxnl2 −/− mice at 2 months of age was reduced, and was not corrected by gene therapy. At 18-month-old Nxnl2 −/− mice showed brain stigmas of tauopathy, such as oligomerization, phosphorylation and aggregation of TAU. This late-onset tauopathy can be prevented, albeit with modest efficacy, by recombinant AAVs administrated to newborn mice. The Nxnl2 −/− mice have memory dysfunction at 2-months that resembles mild-cognitive impairment and at 18-months exhibit tauopathy, resembling to the progression of Alzheimer's disease. We propose the Nxnl2 −/− mouse is a model to study multistage aged related neurodegenerative diseases. The NXNL2 metabolic and redox signaling is a new area of therapeutic research in neurodegenerative diseases.

The Emergence of the Metabolic Signaling of the Nucleoredoxin-like Genes during Evolution

“…Because the Bsg1 -/-v2 mouse has a mild or absent visual phenotype, we analyzed its retina by immunohistochemistry. We found that the Bsg1 -/-v2 retina displays an increased expression of plasmalemma vesicle-associated protein (PLVAP / MECA-32), a marker used to characterize the Nxnl2 -/mouse (Figure 7K) (Jaillard et al, 2021). The increased expression of this biomarker in vascular endothelial cells of the inner retina resembles what is observed in models of diabetic retinopathy (Sheskey et al, 2021).…”

“…One of the shared developmental aspects of vertebrate and Drosophila eyes is their association with cephalization of the nervous system (Koenig and Gross, 2020). Evolutionary divergence in cis elements may explain why Nxnl2 is also expressed specifically by a subset of cells of the area postrema, a region of the brain at the interface between blood circulation at the cerebrospinal fluid, implicated in the control of glucose supply to the brain (Jaillard et al, 2021).…”

“…In the mouse, the main expression site of Nxnl2 outside the eye is the area postrema, a circumventricular organ composed of fenestrated capillaries at the interface of the cerebrospinal fluid and blood circulation (Léveillard et al, 2021). The Nxnl2 -/mouse has a memory deficit which progresses to a tauopathy during aging, reminiscent of the two phases of Alzheimer's disease progression (Jaillard et al, 2021).…”

The Emergence of Rod-Cone Cellular Interaction

“…In an evolutionary perspective, RdCVFL should precede RdCVF, since the latter has a truncated thioredoxin fold that appeared first ( Leveillard and Ait-Ali, 2017 ). Nxnl1 is expressed specifically in the retina, but its paralogue, Nxnl2 , is also involved in the protection of the function of olfactory sensitive neurons and pyramidal neurons of the hippocampus ( Jaillard et al, 2012 ; Jaillard et al, 2021 ). Nxnl2 also encodes for a trophic factor and a thioredoxin-like protein by alternative splicing ( Figure 1C ).…”

Increased expression of NXNL1 in breast cancer associated with favorable prognostic and high level of immune infiltration.

“…The primary function of RdCVF and RdCVFL is mediate neuronal survival and regulates the phosphorylation of TAU. Therefore, the current research on NXNL1 is mainly focused on the central nervous system [2,3], there are no reports related to cancer, we explore the role and signi cance of NXNL1 in the cancer system, hoping to nd out something helpful.…”