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Small heat-shock protein HSPB1 mutants stabilize microtubules in Charcot-Marie-Tooth neuropathy

Leonardo Almeida-Souza, Bob Asselbergh, Constantin d'Ydewalle, Kristof Moonens, Sofie Goethals, Vicky de Winter, Abdelkarim Azmi, Joy Irobi, Jean-Pierre Timmermans and Kris Gevaert UGent, et al. (2011) JOURNAL OF NEUROSCIENCE. 31(43). p.15320-15328
abstract
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
DISEASE, MUTATIONS, PHOSPHORYLATION, HSP27, NEURODEGENERATION, CELL-PROLIFERATION, DYNAMICS, PERIPHERAL NEUROPATHY
journal title
JOURNAL OF NEUROSCIENCE
J. Neurosci.
volume
31
issue
43
pages
15320 - 15328
Web of Science type
Article
Web of Science id
000296446200011
JCR category
NEUROSCIENCES
JCR impact factor
7.115 (2011)
JCR rank
19/242 (2011)
JCR quartile
1 (2011)
ISSN
0270-6474
DOI
10.1523/JNEUROSCI.3266-11.2011
project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2022794
handle
http://hdl.handle.net/1854/LU-2022794
date created
2012-02-07 17:22:23
date last changed
2013-02-27 09:09:29
@article{2022794,
  abstract     = {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.},
  author       = {Almeida-Souza, Leonardo and Asselbergh, Bob and d'Ydewalle, Constantin and Moonens, Kristof and Goethals, Sofie and de Winter, Vicky and Azmi, Abdelkarim and Irobi, Joy and Timmermans, Jean-Pierre and Gevaert, Kris and Remaut, Han and Van den Bosch, Ludo and Timmerman, Vincent and Janssens, Sophie},
  issn         = {0270-6474},
  journal      = {JOURNAL OF NEUROSCIENCE},
  keyword      = {DISEASE,MUTATIONS,PHOSPHORYLATION,HSP27,NEURODEGENERATION,CELL-PROLIFERATION,DYNAMICS,PERIPHERAL NEUROPATHY},
  language     = {eng},
  number       = {43},
  pages        = {15320--15328},
  title        = {Small heat-shock protein HSPB1 mutants stabilize microtubules in Charcot-Marie-Tooth neuropathy},
  url          = {http://dx.doi.org/10.1523/JNEUROSCI.3266-11.2011},
  volume       = {31},
  year         = {2011},
}

Chicago
Almeida-Souza, Leonardo, Bob Asselbergh, Constantin d’ Ydewalle, Kristof Moonens, Sofie Goethals, Vicky de Winter, Abdelkarim Azmi, et al. 2011. “Small Heat-shock Protein HSPB1 Mutants Stabilize Microtubules in Charcot-Marie-Tooth Neuropathy.” Journal of Neuroscience 31 (43): 15320–15328.
APA
Almeida-Souza, L., Asselbergh, B., d’ Ydewalle, C., Moonens, K., Goethals, S., de Winter, V., Azmi, A., et al. (2011). Small heat-shock protein HSPB1 mutants stabilize microtubules in Charcot-Marie-Tooth neuropathy. JOURNAL OF NEUROSCIENCE, 31(43), 15320–15328.
Vancouver
1.
Almeida-Souza L, Asselbergh B, d’ Ydewalle C, Moonens K, Goethals S, de Winter V, et al. Small heat-shock protein HSPB1 mutants stabilize microtubules in Charcot-Marie-Tooth neuropathy. JOURNAL OF NEUROSCIENCE. 2011;31(43):15320–8.
MLA
Almeida-Souza, Leonardo, Bob Asselbergh, Constantin d’ Ydewalle, et al. “Small Heat-shock Protein HSPB1 Mutants Stabilize Microtubules in Charcot-Marie-Tooth Neuropathy.” JOURNAL OF NEUROSCIENCE 31.43 (2011): 15320–15328. Print.