A clinical phenotype of distal hereditary motor neuronopathy type II with a novel HSPB1 mutation

Ikeda, Yoshihisa; Abe, Akiko; Ishida, Chiho; Takahashi, Kazuya; Hayasaka, Kiyoshi; Yamada, Masahito

doi:10.1016/j.jns.2008.09.031

Cited by 47 publications

(27 citation statements)

References 19 publications

(37 reference statements)

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“…At present, mutations in 10 different HSPB1 residues are known to cause CMT neuropathy (Houlden et al, 2008;Ikeda et al, 2009). We tested the five different mutations originally described by Evgrafov et al (2004) and found that three of these mutations displayed an MT stabilization effect.…”

Section: Discussionmentioning

confidence: 99%

Small Heat-Shock Protein HSPB1 Mutants Stabilize Microtubules in Charcot-Marie-Tooth Neuropathy

Almeida-Souza¹,

Asselbergh²,

d’Ydewalle³

et al. 2011

J. Neurosci.

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Mutations in the small heat shock protein HSPB1 (HSP27) are causative for Charcot-Marie-Tooth (CMT) neuropathy. We previously showed that a subset of these mutations displays higher chaperone activity and enhanced affinity to client proteins. We hypothesized that this excessive binding property might cause the HSPB1 mutant proteins to disturb the function of proteins essential for the maintenance or survival of peripheral neurons. In the present work, we explored this hypothesis further and compared the protein complexes formed by wild-type and mutant HSPB1. Tubulin came out as the most striking differential interacting protein, with hyperactive mutants binding more strongly to both tubulin and microtubules. This anomalous binding leads to a stabilization of the microtubule network in a microtubule-associated protein-like manner as reflected by resistance to cold depolymerization, faster network recovery after nocodazole treatment, and decreased rescue and catastrophe rates of individual microtubules. In a transgenic mouse model for mutant HSPB1 that recapitulates all features of CMT, we could confirm the enhanced interaction of mutant HSPB1 with tubulin. Increased stability of the microtubule network was also clear in neurons isolated from these mice. Since neuronal cells are particularly vulnerable to disturbances in microtubule dynamics, this mechanism might explain the neuron-specific CMT phenotype caused by HSPB1 mutations.

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Section: Discussionmentioning

confidence: 99%

Small Heat-Shock Protein HSPB1 Mutants Stabilize Microtubules in Charcot-Marie-Tooth Neuropathy

Almeida-Souza¹,

Asselbergh²,

d’Ydewalle³

et al. 2011

J. Neurosci.

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“…Another form of DRM arises from a deletion mutation (Q151X) in Bc [236]. Similarly, several other naturally-occurring mutations in the C-terminal region of Hsp27; P182L [229], P182S [237], R140G [238] and K141Q [239] cause distal HMN. Other rarer forms of fibrillar neuropathy have been identified, with deletions in the gene encoding Bc (CRYAB) resulting in the absence of the protein from affected muscle fibres [240].…”

Section: Mutations In the C-terminal Regionmentioning

confidence: 99%

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

Treweek

Meehan

Ecroyd

et al. 2014

Cell. Mol. Life Sci.

175

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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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“…2004). The list of variations associated with CMT and HMNs has greatly expanded and nowadays includes mutations which are propagated in both autosomal dominant and recessive manner (Houlden et al 2008;Ikeda et al 2009;Kim et al 2015;Nakhro et al 2013;Stancanelli et al 2015). The recent generation of mouse models has provided novel insights concerning the relation between HSP mutations and CMT.…”

Section: Shsps In Motor Neuropathiesmentioning

confidence: 99%

Small heat shock proteins in ageing and age-related diseases

Charmpilas

Kyriakakis

Tavernarakis

2017

Cell Stress and Chaperones

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Small heat shock proteins (sHSPs) are gatekeepers of cellular homeostasis across species, preserving proteome integrity under stressful conditions. Nonetheless, recent evidence suggests that sHSPs are more than molecular chaperones with merely auxiliary role. In contrast, sHSPs have emerged as central lifespan determinants, and their malfunction has been associated with the manifestation of neurological disorders, cardiovascular disease and cancer malignancies. In this review, we focus on the role of sHSPs in ageing and ageassociated diseases and highlight the most prominent paradigms, where impairment of sHSP function has been implicated in human pathology.

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A clinical phenotype of distal hereditary motor neuronopathy type II with a novel HSPB1 mutation

Cited by 47 publications

References 19 publications

Small Heat-Shock Protein HSPB1 Mutants Stabilize Microtubules in Charcot-Marie-Tooth Neuropathy

Small Heat-Shock Protein HSPB1 Mutants Stabilize Microtubules in Charcot-Marie-Tooth Neuropathy

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

Small heat shock proteins in ageing and age-related diseases

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