Implications of HSPBs and BAG3 in neuro/muscular-protein aggregate diseases

The mammalian family of small heat shock proteins (sHSP/HSPB) consists of ten members (HSPB1-HSPB10), which display different expression profiles and different functions. While some members exert mainly refolding activities and have very poor or no anti-aggregation properties (e.g. HSPB1, HSPB4), other members display strong anti-aggregation function (e.g. HSPB7, HSPB8). Moreover, other members seem to exert specialized activities (e.g. HSPB2 and HSPB3 modulate muscle differentiation). Besides these different aspects, the HSPBs also have common properties and alteration of these properties/functions seem to represent a key mechanism leading to disease. In fact, mutations in HSPB1, HSPB3, HSPB4, HSPB5 and HSPB8, as well as the HSPB8 partner BAG3, cause neurological or muscular disorders. These mutations can lead to disease via a gain of function (GOF) mechanism (due to protein instability and tendency to aggregate), or via a loss of function (LOF) mechanism, which can occur as a direct consequence of the GOF or separately (e.g. mutations leading to a truncated non-functional HSPB protein). In parallel, boosting the function of specific HSPBs and their partners (e.g. BAG3) may represent an attractive approach to combat protein aggregate diseases. How alteration (mutation) or modulation (upregulation) of HSPB and BAG3 function may either lead to or combat disease with a special focus on the intracellular pathways crucial for their activity will be addressed here