Cited by 102Heat shock proteins researchAmyotrophic Lateral Sclerosis ResearchGenetic Neurodegenerative Diseases

Transcriptional induction of the heat shock protein B8 mediates the clearance of misfolded proteins responsible for motor neuron diseases

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Crippa, Valeria, D’Agostino, Vito G., Cristofani, Riccardo, Rusmini, Paola, Cicardi, Maria E., Messi, Elio, Loffredo, Rosa, Pancher, Michael +7 more·2016·Scientific Reports

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.

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  • HSPB8 overexpression enhances autophagic clearance of TARDBP via elevations in TFEB, SQSTM1, and LC3.

    “HSPB8 overexpression also enhances autophagic clearance of TARDBP via elevations in TFEB, SQSTM1, and LC3 [355,356].”

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Authors
Crippa, V., D’Agostino, V. G., Cristofani, R., Rusmini, P., Cicardi, M. E., Messi, E., Loffredo, R., Pancher, M., Piccolella, M., Galbiati, M., Meroni, M., Cereda, C., Carra, S., Provenzani, A., & Poletti, A.
Affiliations
  • Fondazione Istituto Neurologico Nazionale Casimiro Mondino (IT)
  • University of Trento (IT)
  • University of Milan (IT)
  • University of Modena and Reggio Emilia (IT)
Corresponding author
Poletti, Angelo
Venue
Scientific Reports
Published
2016-03-10
Volume
6
Issue
1
Pages
22827-22827
ISSN
2045-2322 (ISSN-L)
OpenAlex
W2296135919
Cited by
101
References
87
Citations by year
2026: 4 · 2025: 8 · 2024: 8 · 2023: 6 · 2022: 14 · 2021: 7 · 2020: 13 · 2019: 11 · 2018: 13 · 2017: 14 · 2016: 2 · 2015: 1
FWCI
6.93
Type
journal article
Language
en
Open access
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
  • Institutional Research Information System (Università degli Studi di Trento) (submittedVersion, cc-by)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
Funders
  • Università degli Studi di Milano
  • EU Joint Programme – Neurodegenerative Disease Research
  • Fondazione Telethon (GGP14039)
  • Fondazione Cariplo (GGP14039, 2014-0686)
  • Ministero della Salute (GR-2011-02347198)
  • Ministero dell’Istruzione, dell’Università e della Ricerca
  • Regione Lombardia
  • Hsinchu Science Park Bureau, Ministry of Science and Technology, Taiwan
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords
HSPB8, TDP-43, amyotrophic lateral sclerosis, motor neuron disease, neurodegeneration, misfolded protein clearance, autophagy, BAG3, colchicine, doxorubicin, TFEB, p62, LC3, small molecule screening, transcriptional induction
MeSH terms
Amyotrophic Lateral Sclerosis, Animals, Autophagy, Cell Line, Colchicine, DNA-Binding Proteins, Doxorubicin, Heat-Shock Proteins, Humans, Motor Neurons, Peptide Fragments, Transcription, Genetic, Protein Serine-Threonine Kinases, Protein Folding, Molecular Chaperones, Heat-Shock Response, Mice, High-Throughput Screening Assays, Frontotemporal Dementia

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