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

• DOI: 10.1038/srep22827
• Publication Date: 2016-03-10T10:10:46Z
• Authors: Valeria Crippa; Vito G. D’Agostino; Riccardo Cristofani; Paola Rusmini; Maria E. Cicardi; Elio Messi; Rosa Loffredo; Michael Pancher; Margherita Piccol...; Mariarita Galbiati; Marco Meroni; Cristina Cereda; Serena Carra; Alessandro Proven...; Angelo Poletti
• Keywords: Aggresome; Chaperone (clinical); Colchicine; BAG3; Stress granule; HSF1; Proteostasis

Abstract Neurodegenerative diseases (NDs) are often associated with the presence of misfolded protein inclusions. The chaperone HSPB8 is upregulated in mice, human brain and muscle structures affected during NDs progression. exerts a potent pro-degradative activity on several proteins responsible for familial forms. Here, we demonstrated that also counteracts accumulation aberrantly localized forms TDP-43 its 25 KDa fragment involved most sporadic cases Amyotrophic Lateral Sclerosis (sALS) Fronto Temporal Dementia (FLTD). acts BAG3 HSP70/HSC70-CHIP complex enhancing autophagic removal proteins. We performed high-through put screening (HTS) to find small molecules capable inducing neurons therapeutic purposes. identified two compounds, colchicine doxorubicin, robustly up-regulated expression. Both doxorubicin increased expression master regulator autophagy TFEB, linker p62/SQSTM1 autophagosome component LC3. In line, both drugs counteracted TDP-25 species motoneuronal death sALS. Thus, analogs able induce better safety tolerability may result beneficial models.