A weakened interface in the P182L variant of HSP27 associated with severe Charcot‐Marie‐Tooth neuropathy causes aberrant binding to interacting proteins

Alderson, T. Reid; Adriaenssens, Elias; Asselbergh, Bob; Pritišanac, Iva; Lent, Jonas Van; Gastall, Heidi Y.; Wälti, Marielle A.; Louis, John M.; Timmerman, Vincent; Baldwin, Andrew J.; Benesch, Justin L. P.

doi:10.15252/embj.2019103811

Cited by 14 publications

(30 citation statements)

References 124 publications

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“…A second example of a gene-specific phenotype is the formation of HSPB1-positive aggregates due to C-terminal HSPB1 mutations. 21 We validated the presence of HSPB1 aggregates in our iPSC-derived motor neurons from the HSPB1 P182L line, using immunostaining at Day 37 for HSPB1 ( Supplementary Fig. 3 A).…”

Section: Resultsmentioning

confidence: 86%

Induced pluripotent stem cell-derived motor neurons of CMT type 2 patients reveal progressive mitochondrial dysfunction

Lent

Verstraelen

Asselbergh

et al. 2021

Brain

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Axonal Charcot-Marie-Tooth neuropathies (CMT type 2) are caused by inherited mutations in various genes functioning in different pathways. The type of genes and multiplicity of mutations reflect the clinical and genetic heterogeneity in CMT2 disease, which complicates the diagnosis and has halted therapy development. Here, we used CMT2 patient-derived pluripotent stem cells (iPSCs) to identify common hallmarks of axonal degeneration shared by different CMT2 subtypes. We compared the cellular phenotypes of neurons differentiated from CMT2 patient iPSCs with those from healthy controls and a CRISPR/Cas9-corrected isogenic line. Our results demonstrate neurite network alterations along with extracellular electrophysiological abnormalities in the differentiated motor neurons. Progressive deficits in mitochondrial and lysosomal trafficking, as well as in mitochondrial morphology, were observed in all CMT2 patient lines. Differentiation of the same CMT2 iPSC-lines into peripheral sensory neurons, only gave rise to cellular phenotypes in subtypes with sensory involvement, supporting the notion that some gene mutations predominantly affect motor neurons. We revealed a common mitochondrial dysfunction in CMT2-derived motor neurons, supported by alterations in the expression pattern and oxidative phosphorylation, which could be recapitulated in the sciatic nerve tissue of a symptomatic mouse model. Inhibition of a dual leucine zipper kinase (DLK) could partially ameliorate the mitochondrial disease phenotypes in CMT2 subtypes. Altogether, our data reveals shared cellular phenotypes across different CMT2 subtypes and suggests that targeting such common pathomechanisms could allow the development of a uniform treatment for CMT2.

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Section: Resultsmentioning

confidence: 86%

Induced pluripotent stem cell-derived motor neurons of CMT type 2 patients reveal progressive mitochondrial dysfunction

Lent

Verstraelen

Asselbergh

et al. 2021

Brain

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“…Since the major aspect regulating HSPB1 activity relies on its self-association and dissociation, dimerization and oligomerization dynamics have been investigated as one of the primary features possibly altered in the mutant protein. In vitro, biochemical studies on HSPB1 mutations falling in different regions of the protein sequence revealed a common tendency to form larger oligomers, often accompanied by a decreased chaperone activity in respect to the HSPB1 wild-type (WT); in vitro analyses also reported a destabilization of the quaternary structure of mutated HSPB1 (Nefedova et al, 2013a;Nefedova et al, 2013b;Chalova et al, 2014b;Muranova et al, 2015;Alderson et al, 2021). Clustering HSPB1 mutations through a domain-dysfunction linkage is not unequivocal, due to contrasting observations resulted from different techniques and assays used to study mutations localized in the same HSPB1 region (Almeida-Souza et al, 2010;Ylikallio et al, 2015;Echaniz-Laguna et al, 2017a).…”

Section: Hspb1mentioning

confidence: 99%

Insights on Human Small Heat Shock Proteins and Their Alterations in Diseases

Tedesco

Cristofani

Ferrari

et al. 2022

Front. Mol. Biosci.

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The family of the human small Heat Shock Proteins (HSPBs) consists of ten members of chaperones (HSPB1-HSPB10), characterized by a low molecular weight and capable of dimerization and oligomerization forming large homo- or hetero-complexes. All HSPBs possess a highly conserved centrally located α-crystallin domain and poorly conserved N- and C-terminal domains. The main feature of HSPBs is to exert cytoprotective functions by preserving proteostasis, assuring the structural maintenance of the cytoskeleton and acting in response to cellular stresses and apoptosis. HSPBs take part in cell homeostasis by acting as holdases, which is the ability to interact with a substrate preventing its aggregation. In addition, HSPBs cooperate in substrates refolding driven by other chaperones or, alternatively, promote substrate routing to degradation. Notably, while some HSPBs are ubiquitously expressed, others show peculiar tissue-specific expression. Cardiac muscle, skeletal muscle and neurons show high expression levels for a wide variety of HSPBs. Indeed, most of the mutations identified in HSPBs are associated to cardiomyopathies, myopathies, and motor neuropathies. Instead, mutations in HSPB4 and HSPB5, which are also expressed in lens, have been associated with cataract. Mutations of HSPBs family members encompass base substitutions, insertions, and deletions, resulting in single amino acid substitutions or in the generation of truncated or elongated proteins. This review will provide an updated overview of disease-related mutations in HSPBs focusing on the structural and biochemical effects of mutations and their functional consequences.

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“…Another structurally notable feature of the ACD is the β4/β8 groove which includes a hydrophobic pocket centered between β-strands 4 and 8 and is located on the outer edge of the ACD β-sandwich (Ehrnsperger et al, 1997 ; Klevit, 2020 ; Reid Alderson et al, 2021 ; Figure 3C ). Therefore, within a dimer of Hsp27 there are two hydrophobic grooves located at the edges of each monomer and one shared dimer interface groove created by the linkage of two monomers (Clouser et al, 2019 ; Boelens, 2020 ; Figure 3D ).…”

Section: Introductionmentioning

confidence: 99%

“…This is described as an extended formation of the CTR in the trans-conformation as the canonical proline can undergo cis-trans isomerization about the I-P peptide bond (Alderson et al, 2017 ). The interaction is found to occur within the same dimeric subunit and between adjacent dimers as well (Reid Alderson et al, 2021 ). The lowly populated residual β-strand structure may further encourage binding between the ACD and CTR and other binding partners (Alderson et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

“…The lowly populated residual β-strand structure may further encourage binding between the ACD and CTR and other binding partners (Alderson et al, 2017 ). The IXI/V motif is considered a short linear motif (SLiM) that modulates interactions between proteins (Reid Alderson et al, 2021 ). In the case of Hsp27, those interactions are between the CTR, the ACD, and possibly client proteins (Reid Alderson et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Insights Into the Role of Heat Shock Protein 27 in the Development of Neurodegeneration

Holguin

Hildenbrand

Bernal

2022

Front. Mol. Neurosci.

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Small heat shock protein 27 is a critically important chaperone, that plays a key role in several essential and varied physiological processes. These include thermotolerance, apoptosis, cytoskeletal dynamics, cell differentiation, protein folding, among others. Despite its relatively small size and intrinsically disordered termini, it forms large and polydisperse oligomers that are in equilibrium with dimers. This equilibrium is driven by transient interactions between the N-terminal region, the α-crystallin domain, and the C-terminal region. The continuous redistribution of binding partners results in a conformationally dynamic protein that allows it to adapt to different functions where substrate capture is required. However, the intrinsic disorder of the amino and carboxy terminal regions and subsequent conformational variability has made structural investigations challenging. Because heat shock protein 27 is critical for so many key cellular functions, it is not surprising that it also has been linked to human disease. Charcot-Marie-Tooth and distal hereditary motor neuropathy are examples of neurodegenerative disorders that arise from single point mutations in heat shock protein 27. The development of possible treatments, however, depends on our understanding of its normal function at the molecular level so we might be able to understand how mutations manifest as disease. This review will summarize recent reports describing investigations into the structurally elusive regions of Hsp27. Recent insights begin to provide the required context to explain the relationship between a mutation and the resulting loss or gain of function that leads to Charcot-Marie Tooth disease and distal hereditary motor neuropathy.

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A weakened interface in the P182L variant of HSP27 associated with severe Charcot‐Marie‐Tooth neuropathy causes aberrant binding to interacting proteins

Cited by 14 publications

References 124 publications

Induced pluripotent stem cell-derived motor neurons of CMT type 2 patients reveal progressive mitochondrial dysfunction

Induced pluripotent stem cell-derived motor neurons of CMT type 2 patients reveal progressive mitochondrial dysfunction

Insights on Human Small Heat Shock Proteins and Their Alterations in Diseases

Insights Into the Role of Heat Shock Protein 27 in the Development of Neurodegeneration

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