title: GPNMB ameliorates mutant TDP-43-induced motor neuron cell death.
abstract: Glycoprotein nonmetastatic melanoma protein B (GPNMB) aggregates are observed in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, but the detailed localization is still unclear. Mutations of transactive response DNA binding protein 43kDa (TDP-43) are associated with neurodegenerative diseases including ALS. In this study, we evaluated the localization of GPNMB aggregates in the spinal cord of ALS patients and the effect of GPNMB against mutant TDP-43 induced motor neuron cell death. GPNMB aggregates were not localized in the glial fibrillary acidic protein (GFAP)-positive astrocyte and ionized calcium binding adaptor molecule-1 (Iba1)-positive microglia. GPNMB aggregates were localized in the microtubule-associated protein 2 (MAP-2)-positive neuron and neurofilament H non-phosphorylated (SMI-32)-positive neuron, and these were co-localized with TDP-43 aggregates in the spinal cord of ALS patients. Mock or TDP-43 (WT, M337V, and A315T) plasmids were transfected into mouse motor neuron cells (NSC34). The expression level of GPNMB was increased by transfection of mutant TDP-43 plasmids. Recombinant GPNMB ameliorated motor neuron cell death induced by transfection of mutant TDP-43 plasmids and serum-free stress. Furthermore, the expression of phosphorylated ERK1/2 and phosphorylated Akt were decreased by this stress, and these expressions were increased by recombinant GPNMB. These results indicate that GPNMB has protective effects against mutant TDP-43 stress via activating the ERK1/2 and Akt pathways, and GPNMB may be a therapeutic target for TDP-43 proteinopathy in familial and sporadic ALS. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nagahara
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Ohuchi
authors.affiliation: Department of Pathology, Brain Research Institute, University of Niigata, Niigata, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Ito
authors.affiliation: Department of Pathology, Brain Research Institute, University of Niigata, Niigata, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsuruma
authors.affiliation: Department of Pathology, Brain Research Institute, University of Niigata, Niigata, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D000818:Animals; D002135:Calcium-Binding Proteins; D016923:Cell Death / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D016900:Neurofilament Proteins / Q000378:metabolism; D066329:Protein Aggregates / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013116:Spinal Cord / Q000473:pathology*
chemical_list: C112986:AIF1 protein, human; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; C503042:GPNMB protein, human; D005904:Glial Fibrillary Acidic Protein; C489788:MAP2 protein, human; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D016900:Neurofilament Proteins; D066329:Protein Aggregates; C000598624:TARDBP protein, human; C051774:neurofilament protein H; D051057:Proto-Oncogene Proteins c-akt
keywords: Amyotrophic lateral sclerosis (ALS); Glycoprotein nonmetastatic melanoma protein B (GPNMB); Sporadic ALS patient; Transactive response DNA binding protein 43kDa (TDP-43); mouse motor neuron cells (NSC34)