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.
Upregulation of HSPB8 as potential therapeutic approach in Amyotrophic Lateral Sclerosis / Carra, Serena. - (2014). (Intervento presentato al convegno The small HSP world tenutosi a Quebec city, Canada nel 2-5 ottobre 2014).
Upregulation of HSPB8 as potential therapeutic approach in Amyotrophic Lateral Sclerosis
CARRA, Serena
2014
Abstract
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.
Pubblicazioni consigliate
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris
