Several neurodegenerative diseases are characterized by the accumulation of aggregates. Boosting aggregate clearance by proteasome and autophagy, with the assistance of chaperones, exerts protective functions in these diseases. We focus on the HSPB8-BAG3-Hsp70 chaperone complex. In cells HSPB8 reduces the aggregation of a truncated form of TDP43 associated with ALS (Crippa 2010). First, we tested whether overexpression of HSP67Bc (Drosophila HSPB8) decreases TDP43-mediated toxicity in vivo, using Drosophila expressing mutated or truncated TDP43. HSP67Bc decreases the eye degeneration caused by NLS-TDP43, which by accumulating in the cytosol causes toxicity (Ritson 2010). This correlates with a reduction of NLS-TDP43 protein levels mediated by HSP67Bc. Inversely, silencing HSP67Bc increases both NLS-TDP43 and ubiquitinated proteins levels, suggesting that HSP67Bc participates to proteostasis. Next, we used flies expressing a truncated form of TDP43 (TDP35), which causes pupae lethality (similarly to truncated TDP25; Gregory 2012). Co-expression of HSP67Bc with TDP35 rescued pupae lethality, further supporting its protective role in vivo. We then asked how mechanistically HSPB8 protects against TDP43-mediated toxicity. Recent studies revealed the presence of RNA-binding proteins component of stress granules (SG) in the proteinaceous inclusions. SGs are mRNA-protein aggregates induced by stress, which serve prosurvival functions. Interestingly, autophagy and specific chaperones indirectly assist SG dynamics (Buchan 2013; Seguin 2014). We investigated whether the HSPB8-BAG3-Hsp70 complex, may indirectly modulate SG dynamics. Intriguingly, upon stress HSPB8 is recruited into SG whereas BAG3 colocalizes with ubiquitinated defective ribosomal products, which are excluded from, but adjacent to SG. Our data open the possibility that HSPB8 and BAG3 may contribute to regulate both protein clearance and SG dynamics, thereby assisting restoration of protein and RNA homeostasis.
OVEREXPRESSION OF HSPB8 PROTECTS AGAINST TDP43-MEDIATED TOXICITY IN DROSOPHILA / Ganassi, Massimo; Diacci, Chiara; Seguin, SAMUEL JOSEPH ANDRE'; Zelotti, Elena; Morelli, FEDERICA FRANCESCA; Crippa, Valeria; Poletti, Angelo; Gregory, Jenna M; Dobson, Christopher M; Pandey, Udai B; Carra, Serena. - (2015). ((Intervento presentato al convegno VI Meeting on the Molecular Mechanisms of Neurodegeneration tenutosi a Milano, Italia nel 28-30 Maggio 2015.
|Data di pubblicazione:||2015|
|Titolo:||OVEREXPRESSION OF HSPB8 PROTECTS AGAINST TDP43-MEDIATED TOXICITY IN DROSOPHILA|
|Autore/i:||Ganassi, Massimo; Diacci, Chiara; Seguin, SAMUEL JOSEPH ANDRE'; Zelotti, Elena; Morelli, FEDERICA FRANCESCA; Crippa, Valeria; Poletti, Angelo; Gregory, Jenna M; Dobson, Christopher M; Pandey, Udai B; Carra, Serena|
|Nome del convegno:||VI Meeting on the Molecular Mechanisms of Neurodegeneration|
|Data del convegno:||28-30 Maggio 2015|
|Luogo del convegno:||Milano, Italia|
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