| Autor: |
Neumann S; Department of Biochemistry II-Molecular Neurobiochemistry, Faculty of Chemistry and Biochemistry, Ruhr-Universität Bochum, 44801 Bochum, Germany., Kuteykin-Teplyakov K; Department of Biochemistry II-Molecular Neurobiochemistry, Faculty of Chemistry and Biochemistry, Ruhr-Universität Bochum, 44801 Bochum, Germany., Heumann R; Department of Biochemistry II-Molecular Neurobiochemistry, Faculty of Chemistry and Biochemistry, Ruhr-Universität Bochum, 44801 Bochum, Germany. |
| Jazyk: |
angličtina |
| Zdroj: |
International journal of molecular sciences [Int J Mol Sci] 2024 Mar 06; Vol. 25 (5). Date of Electronic Publication: 2024 Mar 06. |
| DOI: |
10.3390/ijms25053030 |
| Abstrakt: |
The small GTPase RAS acts as a plasma membrane-anchored intracellular neurotrophin counteracting neuronal degeneration in the brain, but the underlying molecular mechanisms are largely unknown. In transgenic mice expressing constitutively activated V12-Ha-RAS selectively in neurons, proteome analysis uncovered a 70% decrease in voltage-dependent anion channel-1 (VDAC-1) in the cortex and hippocampus. We observed a corresponding reduction in the levels of mRNA splicing variant coding for plasma membrane-targeted VDAC-1 (pl-VDAC-1) while mRNA levels for mitochondrial membrane VDAC-1 (mt-VDAC-1) remained constant. In primary cortical neurons derived from V12-Ha-RAS animals, a decrease in pl-VDAC-1 mRNA levels was observed, accompanied by a concomitant reduction in the ferricyanide reductase activity associated with VDAC-1 protein. Application of MEK inhibitor U0126 to transgenic cortical neurons reconstituted pl-VDAC-1 mRNA to reach wild-type levels. Excitotoxic glutamate-induced cell death was strongly attenuated in transgenic V12-Ha-RAS overexpressing cortical cultures. Consistently, a neuroprotective effect could also be achieved in wild-type cortical cultures by the extracellular application of channel-blocking antibody targeting the N-terminus of VDAC-1. These results may encourage novel therapeutic approaches toward blocking pl-VDAC-1 by monoclonal antibody targeting for complementary treatments in transplantation and neurodegenerative disease. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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