The metabolic signaling of the nucleoredoxin-like 2 gene supports brain function
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 a...
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2021
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oai:doaj.org-article:ad3fc9da614f44d681064fa163f7b7dd2021-12-02T05:01:31ZThe metabolic signaling of the nucleoredoxin-like 2 gene supports brain function2213-231710.1016/j.redox.2021.102198https://doaj.org/article/ad3fc9da614f44d681064fa163f7b7dd2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S221323172100358Xhttps://doaj.org/toc/2213-2317The 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.Céline JaillardFarah OuechtatiEmmanuelle ClérinGéraldine Millet-PuelMariangela CorsiNajate Aït-AliFrédéric BlondQuentin ChevyLara GalesMélissa FarinelliDeniz DalkaraJosé-Alain SahelJean-Charles PortaisJean-Christophe PoncerThierry LéveillardElsevierarticleGlucose metabolismThioredoxinTauopathyLong-term potentiationMetabolomicsHippocampusMedicine (General)R5-920Biology (General)QH301-705.5ENRedox Biology, Vol 48, Iss , Pp 102198- (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Glucose metabolism Thioredoxin Tauopathy Long-term potentiation Metabolomics Hippocampus Medicine (General) R5-920 Biology (General) QH301-705.5 |
| spellingShingle |
Glucose metabolism Thioredoxin Tauopathy Long-term potentiation Metabolomics Hippocampus Medicine (General) R5-920 Biology (General) QH301-705.5 Céline Jaillard Farah Ouechtati Emmanuelle Clérin Géraldine Millet-Puel Mariangela Corsi Najate Aït-Ali Frédéric Blond Quentin Chevy Lara Gales Mélissa Farinelli Deniz Dalkara José-Alain Sahel Jean-Charles Portais Jean-Christophe Poncer Thierry Léveillard The metabolic signaling of the nucleoredoxin-like 2 gene supports brain function |
| description |
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. |
| format |
article |
| author |
Céline Jaillard Farah Ouechtati Emmanuelle Clérin Géraldine Millet-Puel Mariangela Corsi Najate Aït-Ali Frédéric Blond Quentin Chevy Lara Gales Mélissa Farinelli Deniz Dalkara José-Alain Sahel Jean-Charles Portais Jean-Christophe Poncer Thierry Léveillard |
| author_facet |
Céline Jaillard Farah Ouechtati Emmanuelle Clérin Géraldine Millet-Puel Mariangela Corsi Najate Aït-Ali Frédéric Blond Quentin Chevy Lara Gales Mélissa Farinelli Deniz Dalkara José-Alain Sahel Jean-Charles Portais Jean-Christophe Poncer Thierry Léveillard |
| author_sort |
Céline Jaillard |
| title |
The metabolic signaling of the nucleoredoxin-like 2 gene supports brain function |
| title_short |
The metabolic signaling of the nucleoredoxin-like 2 gene supports brain function |
| title_full |
The metabolic signaling of the nucleoredoxin-like 2 gene supports brain function |
| title_fullStr |
The metabolic signaling of the nucleoredoxin-like 2 gene supports brain function |
| title_full_unstemmed |
The metabolic signaling of the nucleoredoxin-like 2 gene supports brain function |
| title_sort |
metabolic signaling of the nucleoredoxin-like 2 gene supports brain function |
| publisher |
Elsevier |
| publishDate |
2021 |
| url |
https://doaj.org/article/ad3fc9da614f44d681064fa163f7b7dd |
| work_keys_str_mv |
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