Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy

Evgrafov, Oleg V.; Mersiyanova, I.V.; Irobi, Joy; Bosch, Ludo Van Den; Dierick, Ines; Leung, Conrad L.; Schagina, O. A.; Verpoorten, Nathalie; Impe, Katrien Van; Федотов, В. П.; Дадали, Е. Л.; Auer‐Grumbach, Michaela; Windpassinger, Christian; Wagner, Klaus; Mitrović, Zoran D.; Hilton‐Jones, David; Talbot, Kevin; Martin, Jean‐Jacques; Вассерман, Н. Н.; Tverskaya, Svetlana; Polyakov, A. V.; Liem, Ronald K.H.; Gettemans, Jan; Robberecht, Wim; Jonghe, Peter De; Timmerman, Vincent

doi:10.1038/ng1354

Cited by 542 publications

(525 citation statements)

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“…Three of these mutations, R127W, S135F (one causing CMT and the other HMN) and R136W, are located in the ACD [229]. Neuronal cells transfected with the mutant Hsp27s are less viable than those expressing wildtype Hsp27 and mutation also leads to altered neurofilament assembly within cells [229].…”

Section: Mutations In the -Crystallin Domainmentioning

confidence: 99%

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

Treweek

Meehan

Ecroyd

et al. 2014

Cell. Mol. Life Sci.

180

177

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Small heat-shock proteins (sHsps) are a diverse family of intra-cellular molecular chaperone proteins that play a critical role in mitigating and preventing protein aggregation under stress conditions such as elevated temperature, oxidation and infection. In doing so, they assist in the maintenance of protein homeostasis (proteostasis) thereby avoiding the deleterious effects that result from loss of protein function and/or protein aggregation. The chaperone properties of sHsps are therefore employed extensively in many tissues to prevent the development of diseases associated with protein aggregation. Significant progress has been made of late in understanding the structure and chaperone mechanism of sHsps. In this review, we discuss some of these advances, with a focus on mammalian sHsp hetero-oligomerisation, the mechanism by which sHsps act as molecular chaperones to prevent both amorphous and fibrillar protein aggregation, and the role of posttranslational modifications in sHsp chaperone function, particularly in the context of disease. 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 2 Abstract (word count = 159)Small heat-shock proteins (sHsps) are a diverse family of intracellular molecular chaperone proteins that play a critical role in preventing protein unfolding, misfolding and aggregation, particularly under stress conditions such as elevated temperature, oxidation and infection. In doing so, they assist in the maintenance of protein homeostasis (proteostasis) and thereby avoid the deleterious effects that result from loss of protein function and/or protein aggregation. The chaperone properties of sHsps are therefore employed extensively in many tissues to prevent the development of diseases associated with protein aggregation. There has been much research into the structure and mechanism of chaperone action of sHsps over approximately the past 30 years, and significant progress has been made of late, however, there are still many unanswered questions relating to these aspects of sHsps. In this review, we outline some of the recent advances in understanding the structure and function of mammalian sHsps, particularly in the context of their many and varied roles in disease.

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Section: Mutations In the -Crystallin Domainmentioning

confidence: 99%

“…Neuronal cells transfected with the mutant Hsp27s are less viable than those expressing wildtype Hsp27 and mutation also leads to altered neurofilament assembly within cells [229]. Similar mutations in the ACD of Hsp22, (i.e.…”

Section: Mutations In the -Crystallin Domainmentioning

confidence: 99%

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

Treweek

Meehan

Ecroyd

et al. 2014

Cell. Mol. Life Sci.

180

177

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“…Furthermore, increased HSP27 levels in transgenic HSP27 mice rescue motor neurons and improve neuromuscular function following nerve injury (Sharp et al, 2006). All these studies suggest for a role of HSP27 in the pathogenesis of motor neuron degeneration.We and others identified mutations in HSP27 and its interacting partner HSP22 (small heat shock 22kDa protein 8: gene symbol HSPB8) in another motor neuron disease, distal hereditary motor neuropathy (distal HMN), supporting their pivotal role in motor neuron function Evgrafov et al, 2004;Tang et al, 2005;Kijima et al, 2005). The specific pathomechanism of these mutant small HSPs is unknown, however in vitro studies demonstrated the formation of intracellular aggregates, abnormal assembly of neurofilaments and a disturbance in axonal transport, pathological hallmarks probably triggering motor neuron death in ALS (Evgrafov et al, 2004;Ackerley et al, 2006).…”

mentioning

confidence: 59%

“…The specific pathomechanism of these mutant small HSPs is unknown, however in vitro studies demonstrated the formation of intracellular aggregates, abnormal assembly of neurofilaments and a disturbance in axonal transport, pathological hallmarks probably triggering motor neuron death in ALS (Evgrafov et al, 2004;Ackerley et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…The neuroprotective effects of HSP27 may be related to its involvement in neurite extension and branching (Williams et al, 2006). Interestingly, mutations in HSPB1 were found in families with inherited peripheral neuropathies, distal HMN and Charcot-Marie-Tooth disease type 2, in particular (Evgrafov et al, 2004;Tang et al, 2005;Kijima et al, 2005). Although these studies strongly suggest a critical biological role for HSP27 in motor neurons, there is no information about the genetic contribution of HSPB1 to the etiology of the major motor neuron disease, sporadic ALS.…”

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Genetic variant in theHSPB1 promoter region impairs the HSP27 stress response

et al. 2007

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The 27kDa heat shock protein 1 (HSP27) is a member of the ubiquitously expressed small heat shock protein family and has pleiotropic cytoprotective functions. Since HSP27 may act as a motor neuron survival factor, we analyzed the genetic contribution of the human HSPB1 gene (HSPB1) to the etiology of amyotrophic lateral sclerosis (ALS). In a cohort of sporadic ALS patients, we identified three rare genetic variations and one of which (c.-217T>C) targeted a conserved nucleotide of the Heat Shock Element (HSE) in the HSPB1 promoter. Since binding of Heat Shock Factor 1 (HSF1) to this HSE is essential for stressinduced transcription of HSPB1, we examined the effect of the c.-217C allele on transcriptional activity and HSF binding. The basal promoter activity of the HSPB1 c.-217C mutant allele decreased to 50% as compared to the wild-type promoter in neuronal and nonneuronal cells. Following heat shock, the HSE variant attenuated significantly the stressrelated increase in transcription. Electrophoretic mobility shift assays demonstrated a dramatically reduced HSF-binding to the c.-217C mutant allele as compared to the c.-217T wild-type allele. In conclusion, our study underscores the importance of the c.-217T nucleotide for HSF binding and heat inducibility of HSPB1. Therefore, our study suggests that the functional HSPB1 variant may represent a genetic modifier in the pathogenesis of motor neuron disease; however, it is necessary to confirm this HSPB1 variant in additional ALS patients. are likely multifactorial processes, including oxidative damage, aggregation, excitotoxicity, inflammation and neurofilament disorganization (Bruijn et al., 2004;Pasinelli and Brown, 2006). Some of these pathogenic processes are known to act as stress stimuli and induce a cellular heat shock response through stress-induced transcription of heat shock proteins (HSPs). Therefore an upregulation of HSPs is seen in several neuronal diseases including ALS (Vleminckx et al., 2002;Bidmon et al., 2004). These HSPs function as molecular chaperones in assisting the correct folding of denatured proteins and by inhibiting cell death pathways. The heat shock 27kDa protein 1 (HSP27: gene symbol HSPB1; MIM# 602195), is a member of the small heat shock protein family and is constitutively expressed in motor neurons (Plumier et al., 1997). Motor neurons upregulate the expression of HSP27 after peripheral nerve transection and this induction is crucial for their survival (Costigan et al., 1998;Benn et al., 2002;Kalmar et al., 2002). There is also increasing evidence for the neuroprotective capacities of HSP27 overexpression; e.g. simultaneous exogenous delivery of HSP27 and HSP70 (gene symbol HSPA1A) protects against copper-zinc superoxide dismutase 1 (SOD1)-mutant induced cell death in mammalian neuronal cells (Bruening et al., 1999;Wagstaff et al., 1999;Wyttenbach et al., 2002;Patel et al., 2005;Batulan et al., 2006), although overexpression of HSP27 alone is insufficient to obtain protection against the toxicity of mutant SOD1 . Furthermore, incr...

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Chaperoning Motor Neurons

Pleasure¹

2005

Arch Neurol

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Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy

Abstract: Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disease and is characterized by

Cited by 542 publications

References 30 publications

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

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

Genetic variant in theHSPB1 promoter region impairs the HSP27 stress response

Chaperoning Motor Neurons

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