title: Transcriptional induction of the heat shock protein B8 mediates the clearance of misfolded proteins responsible for motor neuron diseases.
abstract: Neurodegenerative diseases (NDs) are often associated with the presence of misfolded protein inclusions. The chaperone HSPB8 is upregulated in mice, the human brain and muscle structures affected during NDs progression. HSPB8 exerts a potent pro-degradative activity on several misfolded proteins responsible for familial NDs forms. Here, we demonstrated that HSPB8 also counteracts accumulation of aberrantly localized misfolded forms of TDP-43 and its 25 KDa fragment involved in most sporadic cases of Amyotrophic Lateral Sclerosis (sALS) and of Fronto Lateral Temporal Dementia (FLTD). HSPB8 acts with BAG3 and the HSP70/HSC70-CHIP complex enhancing the autophagic removal of misfolded proteins. We performed a high-through put screening (HTS) to find small molecules capable of inducing HSPB8 in neurons for therapeutic purposes. We identified two compounds, colchicine and doxorubicin, that robustly up-regulated HSPB8 expression. Both colchicine and doxorubicin increased the expression of the master regulator of autophagy TFEB, the autophagy linker p62/SQSTM1 and the autophagosome component LC3. In line, both drugs counteracted the accumulation of TDP-43 and TDP-25 misfolded species responsible for motoneuronal death in sALS. Thus, analogs of colchicine and doxorubicin able to induce HSPB8 and with better safety and tolerability may result beneficial in NDs models.
authors.affiliation: Laboratory of Experimental Neurobiology, C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Crippa
authors.affiliation: Centre for Integrative Biology (CIBIO), Università degli Studi di Trento, Trento, Italy.
authors.forename: Vito G
authors.initials: VG
authors.lastname: D'Agostino
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Cristofani
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rusmini
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano, Italy.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Cicardi
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano, Italy.
authors.forename: Elio
authors.initials: E
authors.lastname: Messi
authors.affiliation: Centre for Integrative Biology (CIBIO), Università degli Studi di Trento, Trento, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Loffredo
authors.affiliation: Centre for Integrative Biology (CIBIO), Università degli Studi di Trento, Trento, Italy.
authors.forename: Michael
authors.initials: M
authors.lastname: Pancher
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Piccolella
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano, Italy.
authors.forename: Mariarita
authors.initials: M
authors.lastname: Galbiati
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Meroni
authors.affiliation: Laboratory of Experimental Neurobiology, C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cereda
authors.affiliation: Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze, Universita' di Modena e Reggio Emilia, Modena, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Carra
authors.affiliation: Centre for Integrative Biology (CIBIO), Università degli Studi di Trento, Trento, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Provenzani
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano, Italy.|Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova, Roma Tor Vergata and Milano, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Poletti
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D002460:Cell Line; D003078:Colchicine / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004317:Doxorubicin / Q000494:pharmacology*; D057180:Frontotemporal Dementia / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D018869:Heat-Shock Response / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000096:biosynthesis; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D010446:Peptide Fragments; C000598624:TARDBP protein, human; C574535:TDP-25 protein, human; D004317:Doxorubicin; D017346:Protein Serine-Threonine Kinases; D003078:Colchicine