title: Mutant SOD1 Increases APP Expression and Phosphorylation in Cellular and Animal Models of ALS.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease and it is the most common adult onset neurodegenerative disorder affecting motor neurons. There is currently no effective treatment for ALS and our understanding of the pathological mechanism is still far away from prevention and/or treatment of this devastating disease. Amyloid precursor protein (APP) is a transmembrane protein that undergoes processing either by β-secretase or α-secretase, followed by γ-secretase. In the present study, we show that APP levels, and aberrant phosphorylation, which is associated with enhanced β-secretase cleavage, are increased in SOD1G93A ALS mouse model. Fluorescence resonance energy transfer (FRET) analysis suggests a close interaction between SOD1 and APP at hippocampal synapses. Notably, SOD1G93A mutation induces APP-SOD1 conformational changes, indicating a crosstalk between these two signaling proteins. Inhibition of APP processing via monoclonal antibody called BBS that blocks APP β-secretase cleavage site, resulted in reduction of mutant SOD1G93A levels in animal and cellular models of ALS, significantly prolonged life span of SOD1G93A mice and diminished inflammation. Beyond its effect on toxic mutant SOD1G93A, BBS treatment resulted in a reduction in the levels of APP, its processing product soluble APPβ and pro-apoptotic p53. This study demonstrates that APP and its processing products contribute to ALS pathology through several different pathways; thus BBS antibody could be a promising neuroprotective strategy for treatment of this disease.
authors.affiliation: Department of Molecular Microbiology & Biotechnology, George S. Wise Faculty of Life Sciences, Tel-Aviv University,Tel-Aviv, Israel.
authors.forename: Polina
authors.initials: P
authors.lastname: Rabinovich-Toidman
authors.affiliation: Department of Molecular Microbiology & Biotechnology, George S. Wise Faculty of Life Sciences, Tel-Aviv University,Tel-Aviv, Israel.
authors.forename: Inna
authors.initials: I
authors.lastname: Rabinovich-Nikitin
authors.affiliation: Department of Molecular Microbiology & Biotechnology, George S. Wise Faculty of Life Sciences, Tel-Aviv University,Tel-Aviv, Israel.
authors.forename: Assaf
authors.initials: A
authors.lastname: Ezra
authors.affiliation: Department of Molecular Microbiology & Biotechnology, George S. Wise Faculty of Life Sciences, Tel-Aviv University,Tel-Aviv, Israel.
authors.forename: Beka
authors.initials: B
authors.lastname: Barbiro
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Hilla
authors.initials: H
authors.lastname: Fogel
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Inna
authors.initials: I
authors.lastname: Slutsky
authors.affiliation: Department of Molecular Microbiology & Biotechnology, George S. Wise Faculty of Life Sciences, Tel-Aviv University,Tel-Aviv, Israel.
authors.forename: Beka
authors.initials: B
authors.lastname: Solomon
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D013569:Synapses / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1