Implications of HSPBs and BAG3 in protein aggregate neuro/muscular 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). Here we will focus on mutations of HSPB3 and HSPB8 and their implication in diseases affecting motor neurons and muscle cells. 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 modulation of specific HSPBs may help to combat disease will be also addressed here.