title: Hexokinase I N-terminal based peptide prevents the VDAC1-SOD1 G93A interaction and re-establishes ALS cell viability.
abstract: Superoxide Dismutase 1 mutants associate with 20-25% of familial Amyotrophic Lateral Sclerosis (ALS) cases, producing toxic aggregates on mitochondria, notably in spinal cord. The Voltage Dependent Anion Channel isoform 1 (VDAC1) in the outer mitochondrial membrane is a docking site for SOD1 G93A mutant in ALS mice and the physiological receptor of Hexokinase I (HK1), which is poorly expressed in mouse spinal cord. Our results demonstrate that HK1 competes with SOD1 G93A for binding VDAC1, suggesting that in ALS spinal cord the available HK1-binding sites could be used by SOD1 mutants for docking mitochondria, producing thus organelle dysfunction. We tested this model by studying the action of a HK1-N-terminal based peptide (NHK1). This NHK1 peptide specifically interacts with VDAC1, inhibits the SOD1 G93A binding to mitochondria and restores the viability of ALS model NSC34 cells. Altogether, our results suggest that NHK1 peptide could be developed as a therapeutic tool in ALS, predicting an effective role also in other proteinopathies.
authors.affiliation: Department of Biological, Geological and Environmental Sciences, Section of Biochemistry and Molecular Biology, University of Catania, Italy.|National Institute of Biostructures and Biosystems (INBB), Italy.|Department of Biomedical and Biotechnological Sciences, University of Catania, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Magrì
authors.affiliation: National Institute of Biostructures and Biosystems (INBB), Italy.|Department of Biomedical and Biotechnological Sciences, University of Catania, Italy.
authors.forename: Ramona
authors.initials: R
authors.lastname: Belfiore
authors.affiliation: Department of Biological, Geological and Environmental Sciences, Section of Biochemistry and Molecular Biology, University of Catania, Italy.|National Institute of Biostructures and Biosystems (INBB), Italy.|Department of Biomedical and Biotechnological Sciences, University of Catania, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Reina
authors.affiliation: CNR Institute of Biostructures and Bioimaging, Catania, Italy.
authors.forename: Marianna Flora
authors.initials: MF
authors.lastname: Tomasello
authors.affiliation: Department of Biological, Geological and Environmental Sciences, Section of Biochemistry and Molecular Biology, University of Catania, Italy.|National Institute of Biostructures and Biosystems (INBB), Italy.
authors.forename: Maria Carmela
authors.initials: MC
authors.lastname: Di Rosa
authors.affiliation: National Institute of Biostructures and Biosystems (INBB), Italy.|Department of Biomedical and Biotechnological Sciences, University of Catania, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Guarino
authors.affiliation: Department of Biological, Geological and Environmental Sciences, Section of Biochemistry and Molecular Biology, University of Catania, Italy.|National Institute of Biostructures and Biosystems (INBB), Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Leggio
authors.affiliation: National Institute of Biostructures and Biosystems (INBB), Italy.|Department of Biomedical and Biotechnological Sciences, University of Catania, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: De Pinto
authors.affiliation: Department of Biological, Geological and Environmental Sciences, Section of Biochemistry and Molecular Biology, University of Catania, Italy.|National Institute of Biostructures and Biosystems (INBB), Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Messina
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006593:Hexokinase / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058990:Molecular Targeted Therapy; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects; D009154:Mutation; D010446:Peptide Fragments / Q000494:pharmacology*; D000072105:Superoxide Dismutase-1 / Q000235:genetics / Q000378:metabolism*; D050995:Voltage-Dependent Anion Channel 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D010446:Peptide Fragments; C000606290:SOD1 protein, human; C494762:VDAC1 protein, human; D000072105:Superoxide Dismutase-1; D050995:Voltage-Dependent Anion Channel 1; C472074:HK1 protein, human; D006593:Hexokinase