Small Heat Shock Proteins and Protein-Misfolding Diseases

Abstract

Small heat shock proteins (sHsps) are molecular chaperones ubiquitously distributed in numerous species, from bacteria to humans. A conserved C-terminal "alpha-crystallin" domain organized in a beta-sheet sandwich and oligomeric structure are common features of sHsps. sHsps protect cells against many kinds of stresses including heat shock, oxidative and osmotic stress. sHsps recognize unfolded proteins, prevent their irreversible aggregation and facilitate refolding of bound substrates in cooperation with ATP-dependent molecular chaperones (Hsp70/Hsp40). Mammalian sHsps (HSPBs) are multifunctional proteins involved in many cellular processes including those which are not directly related to protein folding and aggregation. HSPBs participate in cell development and cancerogenesis, regulate apoptosis and control cytoskeletal architecture. Recent data revealed that HSPBs also play an important role in membrane stabilization. Mutation in HSPB genes have been identified, which are responsible for the development of cataract, desmin related myopathy and neuropathies. HSPBs are often found as components of protein aggregates associated with protein-misfolding disorders, such as Parkinson's, Alzheimer's, Alexander's and prion diseases. It is supposed that the presence of HSPBs in intra- or extracellular protein deposits is a consequence of the chaperone activity of HSPBs, however more studies are needed to reveal the exact function of HSPBs during the formation (or removal) of disease-related aggregates.

Small heat-shock proteins: important players in regulating cellular proteostasis

“…Furthermore, Bc inhibits the aggregation of glial acidic fibrillary protein (GAFP) and -syn which are associated with Alexander and Parkinson's disease (PD) pathologies, respectively [167,168]. Hsp20 and Hsp22 are also present at increased levels following neuronal stress associated with AD, PD, and ALS [169][170][171][172][173]. Hsp27 is also upregulated in AD and Neuman-Pick diseases [70].…”

“…We have previously demonstrated that Bc prevents the aggregation of -syn, the principal protein in Lewy body deposits, and that Bc also binds to intact -syn fibrils 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 to prevent their further growth [106,107,167]. Furthermore, several sHsps (Hsp20, Hsp22, HspB7 and HspB9) inhibit the aggregation of the polyQ huntingtin protein responsible for Huntington disease and also protect against cell death triggered by the deposition of the aberrant protein [173,196]. Our subsequent studies have shown, however, that polyQ aggregation occurs in stages, and while Bc potently inhibits the first stage of fibril formation by the polyQ protein, ataxin (responsible for spinocerebellar ataxia), through interaction with its Josephin domain, the second stage of polyQ aggregation can still proceed [197].…”

“…The increased expression of Bc, along with other Hsps, is proposed to be part of the oligodendrocyte's survival response [180]. Initial studies identifying Bc bound to antibodies in the sera of affected patients suggested Bc as an auto-antigen to human T-cells in MS [173,200,201]. Subsequent studies showed that most of the sHsps (HspB1-8) were capable of binding immunoglobulin molecules with varying affinities and through multiple binding sites [201].…”

Distension of the uterus induces HspB1 expression in rat uterine smooth muscle

“…Heat shock protein (HSP) B1 (HspB1), previously known as Hsp27, is one of 11 members of the mammalian small HSP (sHSP) family (13,22). All members of this class have a molecular weight of 15,000 -40,000 and share a structural domain in their COOH-terminal halves, named the ␣-crystallin domain, that spans two putative actin-binding domains (36).…”

“…All members of this class have a molecular weight of 15,000 -40,000 and share a structural domain in their COOH-terminal halves, named the ␣-crystallin domain, that spans two putative actin-binding domains (36). Furthermore, these proteins have demonstrated ATP-independent chaperone activity (14,22).…”