HSPB2 and HSPB8 prevent ARpolyQ aggregation in motoneuronal model of spinal and bulbar muscular atrophy

Spinal and bulbar muscular atrophy (SBMA) is a motoneuronal disorder caused by an expansion of the polyglutamine (polyQ) tract in the androgen receptor (AR) protein. ARpolyQ misfolds and leads to the formation of intracellular aggregates in a testosterone-dependent manner. ARpolyQ impairs both Ubiquitin-Proteasome (UPP) and Autophagolysosome (APLP) Pathways leading to an accumulation of misfolded proteins and aggregates as well as protein degradation defects. Small heat shock proteins (HSPBs) are chaperones that prevent aggregation of misfolded proteins by assisting their refolding or facilitating their removal through the UPP or APLP. Among the HSPBs, we focused our attention on HSPB8 and HSPB2. HSPB8 is highly expressed in central nervous system and in skeletal muscle. In muscle, HSPB8 forms high molecular weight complexes by interacting with HSPB2. In SBMA motoneuronal cell model, we observed that HSPB8 counteracts ARpolyQ aggregation and facilitates the ARpolyQ clearance. In particular, HspB8 pro-degradative activity does not require a fully functional UPP because HspB8 enhances the mutant ARpolyQ clearance restoring a normal autophagic flux. Interestingly trehalose, an autophagy activator, is able to increase HSPB8 expression suggesting that HSPB8 might be one of the molecular effector of trehalose autophagic activation. We recently found that also HSPB2 is expressed in motoneuronal cell line and its expression, like HSPB8, is highly increased when the UPP is blocked. We analyzed the effects of ARQ(n) over-expression on HSPB2 expression and we found that in presence of testosterone-activated ARpolyQ, HSPB2 expression is highly increased, while HSPB8 expression is unchanged. Interestingly, when overexpressed HSPB2, like HSPB8, counteracts ARpolyQ aggregation. All these data suggest that HSPB2 and HSPB8 might play a relevant role in SBMA. GRANTS Fondazione AriSLA; AFM Telethon Foundation; Regione Lombardia multicentric project