The role of small heat shock proteins HSPB2 and HSPB8 in spinal and bulbar muscular atrophy

Spinal and bulbar muscular atrophy (SBMA) is a motoneuronal disorder caused by a polyglutamine elongation (polyQ) in the androgen receptor (AR) protein. The polyQ mutation is associated with misfolded and aggregated forms of AR. The small heat shock proteins (HSPBs) seem to exert a protective role in different neurodegenerative diseases caused by an accumulation of misfolded proteins facilitating their clearance through the proteolytic pathways We thus tested the potential effects of two specific HSPBs (HSPB2 and HSPB8) to increase ARpolyQ clearance. In SBMA motoneuronal cell lines, we found that HspB8 facilitates the autophagic removal of misfolded aggregating ARpolyQ, preventing the p62 bodies formation and restoring a fully functional autophagic flux. Recent data showed that also HSPB2 counteracts ARpolyQ aggregation in SBMA motoneuronal cell line. Because the lower motoneurons and the skeletal muscle are the main sites of SBMA degeneration, we analyzed the HSPBs expression in SBMA tg mice tissues, using two different mice models. Firstly, we used a SBMA knock-in mice which express ARpolyQ under control of the endogenous AR promoter (provided by A.P. Lieberman). In this model, transgenic AR expression reflects that of the endogenous protein. We observed that HSPB2 and HSPB8 expression are highly induced in muscle tissue. Moreover, we used SBMA transgenic mice in which hARpolyQ expression is driven by prion promoter (provided by D.E. Merry). Using this model, our data showed that HSPB8 expression is selectively increased only in spinal cord where hARpolyQ is highly expressed. Instead in muscle tissue, which do not express hARpolyQ, HSPB8 levels are very low. Thus, HSPB2 and HSPB8 expression is strictly linked to ARpolyQ expression in the tissues, suggesting that they might represent a cellular response to counteract ARpolyQ toxicity. GRANTS Fondazione AriSLA; AFM Telethon Foundation; Regione Lombardia multicentric project