title: The chaperone HSPB8 reduces the accumulation of truncated TDP-43 species in cells and protects against TDP-43-mediated toxicity.
abstract: Aggregation of TAR-DNA-binding protein 43 (TDP-43) and of its fragments TDP-25 and TDP-35 occurs in amyotrophic lateral sclerosis (ALS). TDP-25 and TDP-35 act as seeds for TDP-43 aggregation, altering its function and exerting toxicity. Thus, inhibition of TDP-25 and TDP-35 aggregation and promotion of their degradation may protect against cellular damage. Upregulation of HSPB8 is one possible approach for this purpose, since this chaperone promotes the clearance of an ALS associated fragments of TDP-43 and is upregulated in the surviving motor neurones of transgenic ALS mice and human patients. We report that overexpression of HSPB8 in immortalized motor neurones decreased the accumulation of TDP-25 and TDP-35 and that protection against mislocalized/truncated TDP-43 was observed for HSPB8 in Drosophila melanogaster Overexpression of HSP67Bc, the functional ortholog of human HSPB8, suppressed the eye degeneration caused by the cytoplasmic accumulation of a TDP-43 variant with a mutation in the nuclear localization signal (TDP-43-NLS). TDP-43-NLS accumulation in retinal cells was counteracted by HSP67Bc overexpression. According with this finding, downregulation of HSP67Bc increased eye degeneration, an effect that is consistent with the accumulation of high molecular weight TDP-43 species and ubiquitinated proteins. Moreover, we report a novel Drosophila model expressing TDP-35, and show that while TDP-43 and TDP-25 expression in the fly eyes causes a mild degeneration, TDP-35 expression leads to severe neurodegeneration as revealed by pupae lethality; the latter effect could be rescued by HSP67Bc overexpression. Collectively, our data demonstrate that HSPB8 upregulation mitigates TDP-43 fragment mediated toxicity, in mammalian neuronal cells and flies.
authors.affiliation: Genomic and post-Genomic Center, C. Mondino National Institute of Neurology Foundation, 27100 Pavia, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Crippa
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milano, Italy.
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Cicardi
authors.affiliation: Department of Pediatrics, Division of Child Neurology, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA.|Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA.
authors.forename: Nandini
authors.initials: N
authors.lastname: Ramesh
authors.affiliation: Department of Biomedical, Metabolic and Neuronal Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Seguin
authors.affiliation: Department of Biomedical, Metabolic and Neuronal Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Ganassi
authors.affiliation: Department of Biomedical, Metabolic and Neuronal Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bigi
authors.affiliation: Department of Biomedical, Metabolic and Neuronal Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Diacci
authors.affiliation: Department of Biomedical, Metabolic and Neuronal Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Zelotti
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Madina
authors.initials: M
authors.lastname: Baratashvili
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Jenna M
authors.initials: JM
authors.lastname: Gregory
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: Genomic and post-Genomic Center, C. Mondino National Institute of Neurology Foundation, 27100 Pavia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cereda
authors.affiliation: Department of Pediatrics, Division of Child Neurology, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA.|Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA.
authors.forename: Udai Bhan
authors.initials: UB
authors.lastname: Pandey
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milano, Italy angelo.poletti@unimi.it.
authors.forename: Angelo
authors.initials: A
authors.lastname: Poletti
authors.affiliation: Department of Biomedical, Metabolic and Neuronal Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy serena.carra@unimore.it.
authors.forename: Serena
authors.initials: S
authors.lastname: Carra
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics; D005123:Eye / Q000254:growth & development / Q000503:physiopathology; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D066263:Protein Aggregation, Pathological / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D011679:Pupa / Q000235:genetics / Q000254:growth & development
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; C554551:Hsp67Bc protein, Drosophila; D018832:Molecular Chaperones; D010446:Peptide Fragments; C000598624:TARDBP protein, human; C574535:TDP-25 protein, human; D017346:Protein Serine-Threonine Kinases