Different anti-aggregation and pro-degradative functions of the members of the mammalian sHSP family in neurological disorders

Philosophical Transactions of the Royal Society B: Biological Sciences, May 2013

The family of the mammalian small heat-shock proteins consists of 10 members (sHSPs/HSPBs: HSPB1–HSPB10) that all share a highly conserved C-terminal alpha-crystallin domain, important for the modulation of both their structural and functional properties. HSPB proteins are biochemically classified as molecular chaperones and participate in protein quality control, preventing the aggregation of unfolded or misfolded proteins and/or assisting in their degradation. Thus, several members of the HSPB family have been suggested to be protective in a number of neurodegenerative and neuromuscular diseases that are characterized by protein misfolding. However, the pro-refolding, anti-aggregation or pro-degradative properties of the various members of the HSPB family differ largely, thereby influencing their efficacy and protective functions. Such diversity depends on several factors, including biochemical and physical properties of the unfolded/misfolded client, the expression levels and the subcellular localization of both the chaperone and the client proteins. Furthermore, although some HSPB members are inefficient at inhibiting protein aggregation, they can still exert neuroprotective effects by other, as yet unidentified, manners; e.g. by maintaining the proper cellular redox state or/and by preventing the activation of the apoptotic cascade. Here, we will focus our attention on how the differences in the activities of the HSPB proteins can influence neurodegenerative and neuromuscular disorders characterized by accumulation of aggregate-prone proteins. Understanding their mechanism of action may allow us to target a specific member in a specific cell type/disease for therapeutic purposes.

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Different anti-aggregation and pro-degradative functions of the members of the mammalian sHSP family in neurological disorders

Review Serena Carra 1 2 Paola Rusmini 0 Valeria Crippa 0 Elisa Giorgetti 0 Alessandra Boncoraglio 0 1 Riccardo Cristofani 0 Maximillian Naujock 1 Melanie Meister 1 Melania Minoia 1 Harm H. Kampinga 1 Angelo Poletti 0 0 Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFEB), 'Centro di Eccellenza per lo Studio delle Malattie Neurodegenerative' (CEND), Universita' degli Studi di Milano , via Balzaretti 9, Milano 20133 , Italy 1 Department of Cell Biology, University Medical Center of Groningen, University of Groningen , Antonius Deusinglaan 1, Groningen AV 9713 , The Netherlands 2 Dipartimento di Scienze Biomediche, Universita' degli Studi di Modena e Reggio Emilia , via G. Campi 287, Modena 41125 , Italy The family of the mammalian small heat-shock proteins consists of 10 members (sHSPs/HSPBs: HSPB1 - HSPB10) that all share a highly conserved C-terminal alpha-crystallin domain, important for the modulation of both their structural and functional properties. HSPB proteins are biochemically classified as molecular chaperones and participate in protein quality control, preventing the aggregation of unfolded or misfolded proteins and/or assisting in their degradation. Thus, several members of the HSPB family have been suggested to be protective in a number of neurodegenerative and neuromuscular diseases that are characterized by protein misfolding. However, the pro-refolding, anti-aggregation or pro-degradative properties of the various members of the HSPB family differ largely, thereby influencing their efficacy and protective functions. Such diversity depends on several factors, including biochemical and physical properties of the unfolded/misfolded client, the expression levels and the subcellular localization of both the chaperone and the client proteins. Furthermore, although some HSPB members are inefficient at inhibiting protein aggregation, they can still exert neuroprotective effects by other, as yet unidentified, manners; e.g. by maintaining the proper cellular redox state or/and by preventing the activation of the apoptotic cascade. Here, we will focus our attention on how the differences in the activities of the HSPB proteins can influence neurodegenerative and neuromuscular disorders characterized by accumulation of aggregate-prone proteins. Understanding their mechanism of action may allow us to target a specific member in a specific cell type/disease for therapeutic purposes. 1. Introduction A P d r s g ]9 (a -a Q ,1 i 1 n t ly [ D A g g /s P in ]7 irn ]7 in s te U ] ra [1 la [1 lifsod issaee rtcyao llryaeen [169 lllrtceau iranb llrtcxeau iranb m d ( g x e e D E g ) G je )D in s s N in P lfsod seae ronu llryae CAUHN rkuPn ll(ceN ,][87 . im isd (en eng iP .an U , , l iiirtsccaaon rsve i:rrtt/cxeaeeoodnm ill,rrttsceeeabuumm ii,sscaaopppupnhm r[]co13d i:,rtcxeon i,scaopppuhm ii,rt[]ssccvaee12n r e w w b n lo lo 3 S r ] a y 8 iiitannng illryobfim iirttyeng []42 iten itsssyenh iii;rtonhb taaouphg ilrtsaoum ,[43464 a o r m p s in ly ll Q ld e irttsscyeaon l,,yopPADD i][a44dnm iillcagnPU it(onn iiilr)caongm ,][LS5434A . . P .a .a U n n homo- and hetero-oligomeric complexes [54,55]. The dynamic association/dissociation of the oligomers has been suggested to be key to the function of the HSPB proteins and is often regulated by their phosphorylation state [49,56]. HSPB proteins are biochemically classified as molecular chaperones and participate in protein quality control; in fact, several HSPB family members have been shown to be able to bind to ( partially) unfolded or to misfolded, aggregation-prone proteins [57] preventing their aggregation. In conjunction with ATP-dependent chaperones (e.g. HSP70s/HSPAs), the HSPB-bound clients can either be refolded or degraded; the mechanisms for either refolding or degradation is not fully understood, but may depend both on the state of the client and on the specific HSPB member that is bound to it (see later). The chaperone activity of small HSPs has been discovered and explored mainly in cell-free experiments with purified proteins [58 60] and it accounts for, for example, the role that HSPB4 plays in maintaining eye transparency [26]. Whether this chaperone function is also underlying other cellular functions of HSPB members is less clear. For example, some HSPBs members (e.g. HSPB1 and HSPB5) have the capability to modulate the assembly and stabilization of cytoskeleton components, such as actin and intermediate filaments [22,37,38,41,61 64], but how far these actions rely on their chaperone activity is unknown. It is also not clear whether other HSPB family members serve in cytoskeletal protection or whether different cytoskeletal and contractile elements may require different HSPB members. Other functional endpoints that have been shown to be affected by HSPB members include the maintenance of proper cellular redox state, protecting cells from oxidative stress conditions (HSPB1, [65]), a general anti-apoptotic function (HSPB1, [66,67] (...truncated)


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Serena Carra, Paola Rusmini, Valeria Crippa, Elisa Giorgetti, Alessandra Boncoraglio, Riccardo Cristofani, Maximillian Naujock, Melanie Meister, Melania Minoia, Harm H. Kampinga, Angelo Poletti. Different anti-aggregation and pro-degradative functions of the members of the mammalian sHSP family in neurological disorders, Philosophical Transactions of the Royal Society B: Biological Sciences, 2013, 368/1617, DOI: 10.1098/rstb.2011.0409