Inhibition of α‐synuclein aggregation by small heat shock proteins

Bruinsma, Ilona B.; Bruggink, Kim; Kinast, Karsten; Versleijen, Alexandra A M; Segers-Nolten, Ine; Subramaniam, Vinod; Kuiperij, H. Bea; Boelens, Wilbert C.; Waal, R.M.W. de; Verbeek, Marcel M.

doi:10.1002/prot.23152

Cited by 106 publications

(101 citation statements)

References 54 publications

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“…The ability of Hsp27 (and other sHsps such as αB-c, Hsp20, HspB8 and HspB2/HspB3) to prevent the aggregation of a range of proteins has been well characterized (9,10,37,44,55). We have recently shown that αB-c and Hsp27 interact transiently with monomeric α-syn to prevent its nucleation and subsequent aggregation, a process that is dependent on the aggregation rate (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…However, some mammalian sHsps, including αB-crystallin (αB-c) (HSPB5) and Hsp27 (HSPB1), form large polydisperse oligomeric assemblies that undergo rapid subunit exchange and display chaperone activity (5)(6)(7)(8). Indeed, αB-c and Hsp27 are capable of preventing the aggregation of a wide range of model and disease-relevant amyloidogenic targets (9)(10)(11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

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The small heat shock protein Hsp27 binds α-synuclein fibrils, preventing elongation and cytotoxicity

Cox

Whiten

Brown

et al. 2018

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The small heat shock protein Hsp27 binds α-synuclein fibrils, preventing elongation and cytotoxicity

Cox

Whiten

Brown

et al. 2018

Journal of Biological Chemistry

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“…The potent anti-aggregation properties of the sHsps, αB-c and Hsp27 have been well established in vitro (Bruinsma et al 2011;Cox et al 2016). However, in order to capture the complex factors influencing protein aggregation in the cell, it is essential to complement these in vitro studies with cellular models of aggregation.…”

Section: Discussionmentioning

confidence: 99%

“…Both Hsp27 and αB-c have been shown to be potent inhibitors of α-syn aggregation using in vitro, solution-based assays (Bruinsma et al 2011;Cox et al 2016). However, it remains to be established whether these sHsps can prevent the aggregation of α-syn in cells (Cox et al 2014).…”

Section: Introductionmentioning

confidence: 99%

The small heat shock proteins αB-crystallin (HSPB5) and Hsp27 (HSPB1) inhibit the intracellular aggregation of α-synuclein

Cox

Ecroyd

2017

Cell Stress and Chaperones

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Protein homeostasis, or proteostasis, is the process of maintaining the conformational and functional integrity of the proteome. Proteostasis is preserved in the face of stress by a complex network of cellular machinery, including the small heat shock molecular chaperone proteins (sHsps), which act to inhibit the aggregation and deposition of misfolded protein intermediates. Despite this, the pathogenesis of several neurodegenerative diseases has been inextricably linked with the amyloid fibrillar aggregation and deposition of α-synuclein (α-syn). The sHsps are potent inhibitors of α-syn aggregation in vitro. However, the limited availability of a robust, cellbased model of α-syn aggregation has, thus far, restricted evaluation of sHsp efficacy in the cellular context. As such, this work sought to establish a robust model of intracellular α-syn aggregation using Neuro-2a cells. Aggregation of α-syn was found to be sensitive to inhibition of autophagy and the proteasome, resulting in a significant increase in the proportion of cells containing α-syn inclusions. This model was then used to evaluate the capacity of the sHsps, αB-c and Hsp27, to prevent α-syn aggregation in cells. To do so, we used bicistronic expression plasmids to express the sHsps. Unlike traditional fluorescent fusion constructs, these bicistronic expression plasmids enable only individual transfected cells expressing the sHsps (via expression of the fluorescent reporter) to be analysed, but without the need to tag the sHsp, which can affect its oligomeric structure and chaperone activity. Overexpression of both αB-c and Hsp27 significantly reduced the intracellular aggregation of α-syn. Thus, these findings suggest that overexpressing or boosting the activity of sHsps may be a way of preventing amyloid fibrillar aggregation of α-syn in the context of neurodegenerative disease.

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“…HSPB6 could interact WT and mutant α-syn and inhibit its fibril formation. In his way, HSPB6 protect cells from the toxicity associated with α-syn aggregation [14].…”

Section: Role Of Hspb6 In Neuronal Diseasesmentioning

confidence: 99%

Study of HSPB6: Insights into the Properties of the Multifunctional Protective Agent

Xiao

Zhou

et al. 2017

Cell Physiol Biochem

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HSPB6(Heat shock protein B6), is also referred to as P20/HSP20. Unlike other many other members of sHSP(small Heat shock protein) family, which tend to form high-molecular-mass oligomers, in solution, human HSPB6 only forms dimers. However, it still exhibits chaperon-like activity comparable with that of HSPB5. It is expressed ubiquitously, with high and constitutive expression in muscular tissues. sHSPs characteristically function as molecular chaperones and HSPB6 also has a molecular chaperone activity. HSPB6 is up-regulated in response to diverse cellular stress or damage and protect cells from otherwise lethal conditions. HSPB6 is widely recognized as a principle mediator of cardioprotective signaling and recent studies have unraveled the protective role of HSPB6 in disease or injury to the central nervous system. Moreover, accumulating evidence has implicated HSPB6 as a key mediator of diverse vital physiological processes, such as smooth muscle relaxation, platelet aggregation. The versatility of HSPB6 can be explained by its direct involvement in regulating different client proteins and its ability to form heterooligomer with other sHSPs, which seems to be dependent on HSPB6 phosphorylation. This review focuses on the properties including expression and regulation pattern, phosphorylation, chaperon activity, multiple cellular targets of HSPB6, as well as its possible role in physical and pathological conditions.

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Inhibition of α‐synuclein aggregation by small heat shock proteins

Cited by 106 publications

References 54 publications

The small heat shock protein Hsp27 binds α-synuclein fibrils, preventing elongation and cytotoxicity

The small heat shock protein Hsp27 binds α-synuclein fibrils, preventing elongation and cytotoxicity

The small heat shock proteins αB-crystallin (HSPB5) and Hsp27 (HSPB1) inhibit the intracellular aggregation of α-synuclein

Study of HSPB6: Insights into the Properties of the Multifunctional Protective Agent

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