Homocysteine-lowering gene therapy rescues signaling pathways in brain of mice with intermediate hyperhomocysteinemia

Vanessa Baloula,Marta Fructuoso,Nadim Kassis,Dalale Gueddouri,Jean-Louis Paul,Nathalie Janel

doi:10.1016/j.redox.2018.08.015

Abstract

Hyperhomocysteinemia due to cystathionine beta synthase (CBS) deficiency is associated with diverse cognitive dysfunction. Considering the role of the serine/threonine kinase DYRK1A, not only in developmental defects with life-long structural and functional consequences, but also in multiple neurodegenerative diseases, its protein expression and kinase activity has been analyzed in brain of heterozygous CBS deficient mice and found to be increased. We previously demonstrated that specific liver treatment with an adenovirus expressing Dyrk1A normalizes hepatic DYRK1A level and decreases hyperhomocysteinemia in mice with moderate to intermediate hyperhomocysteinemia. We here use a hepatocyte-specific recombinant adeno-associated viral (AAV) serotype 8-mediated DYRK1A gene therapy (AAV2/8-DYRK1A) to analyze the effect of hepatic Dyrk1A gene transfer on some altered molecular mechanisms in brain of mice with intermediate hyperhomocysteinemia. Our selective hepatic treatment alleviates altered DYRK1A protein level and signaling pathways in brain of mice, the MAPK/ERK and PI3K/Akt pathways initiated by receptor tyrosine kinase, the BDNF dependent TrkB pathway, and NFkB pathway. These results demonstrate the positive effect of AAV2/8-DYRK1A gene transfer on neuropathological and inflammatory processes in brain of mice with intermediate hyperhomocysteinemia.

Highlights

Cystathionine beta-synthase (CBS) deficiency is an inborn error of sulfur amino acid metabolism
We showed that hhcys is accompanied by alterations in signaling pathways initiated by receptor tyrosine kinases (RTK), the ERK and Phosphatidylinositol 3-kinase (PI3K)/Akt pathways, and brain-derived neurotrophic factor/TrkB signaling pathway, in brain of cystathionine beta synthase (CBS) deficient mice, a murine model of hhcy [8,9,10,11,12]
The mRNA expression of DYRK1A was examined by Q-polymerase chain reaction (PCR) and, as previously described [25], even if the difference is not significant, the mRNA expression was increased in liver of mice with intermediate hhcy, when compared with control (CTL) mice (Table 1)

Summary

Introduction

Cystathionine beta-synthase (CBS) deficiency is an inborn error of sulfur amino acid metabolism. CBS catalyzes the conversion of homocysteine (hcy), an intermediate amino acid derived from the metabolism of dietary methionine, to cystathionine in the first step of the transsulfuration pathway. Hyperhomocysteinemia (hhcy), is categorized by range as moderate (15–30 μM), intermediate (30–100 μM), and severe (above 100 μM). The most common form of severe hhcy is that by CBS deficiency. We showed that hhcys is accompanied by alterations in signaling pathways initiated by receptor tyrosine kinases (RTK), the ERK and Phosphatidylinositol 3-kinase (PI3K)/Akt pathways, and brain-derived neurotrophic factor/TrkB signaling pathway, in brain of CBS deficient mice, a murine model of hhcy [8,9,10,11,12]

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Discussion

Conclusion