Protective effects of heat shock protein 27 in a model of ALS occur in the early stages of disease progression

Sharp, Paul; Akbar, Mohammed T.; Bouri, Sonia; Senda, Atsushi; Joshi, Kieran; Chen, Han-Jou; Latchman, David S.; Wells, Dominic J.; Belleroche, Jacqueline de

doi:10.1016/j.nbd.2007.12.002

Cited by 101 publications

(82 citation statements)

References 59 publications

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“…These data indicate that the ability of Hsp27 to suppress SOD1 proteotoxicity in cultured neurons (Patel et al 2005) is likely to be attributable to the chaperone activity of Hsp27. This is consistent with increased survival of motor neurons in early-stage disease in Hsp27 over-expressing SOD1 mice (Sharp et al 2008). The lack of an effect on longevity in this model is most likely attributable to an overwhelming of the chaperone; as disease progressed, Hsp27 levels in motor neurons decreased (Sharp et al 2008).…”

Section: Resultssupporting

confidence: 74%

“…This is consistent with increased survival of motor neurons in early-stage disease in Hsp27 over-expressing SOD1 mice (Sharp et al 2008). The lack of an effect on longevity in this model is most likely attributable to an overwhelming of the chaperone; as disease progressed, Hsp27 levels in motor neurons decreased (Sharp et al 2008).…”

Section: Resultssupporting

confidence: 74%

“…In animal models, knockdown of αB-crystallin does not affect the amount of insoluble SOD1 nor does it significantly alter the lifespan of transgenic mice (Karch and Borchelt 2010). Similarly, while over-expression of Hsp27 slows the early phase of disease, it does not alter the lifespan of SOD1 mice (Sharp et al 2008). This may be, at least in part, due to the fact that robust expression of αB-crystallin and Hsp25 is largely restricted to glial cells.…”

Section: Introductionmentioning

confidence: 99%

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The small heat shock proteins αB-crystallin and Hsp27 suppress SOD1 aggregation in vitro

Yerbury

Gower

Vanags

et al. 2013

Cell Stress and Chaperones

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Amyotrophic lateral sclerosis is a devastating neurodegenerative disease. The mechanism that underlies amyotrophic lateral sclerosis (ALS) pathology remains unclear, but protein inclusions are associated with all forms of the disease. Apart from pathogenic proteins, such as TDP-43 and SOD1, other proteins are associated with ALS inclusions including small heat shock proteins. However, whether small heat shock proteins have a direct effect on SOD1 aggregation remains unknown. In this study, we have examined the ability of small heat shock proteins αB-crystallin and Hsp27 to inhibit the aggregation of SOD1 in vitro. We show that these chaperone proteins suppress the increase in thioflavin T fluorescence associated with SOD1 aggregation, primarily through inhibiting aggregate growth, not the lag phase in which nuclei are formed. αB-crystallin forms high molecular mass complexes with SOD1 and binds directly to SOD1 aggregates. Our data are consistent with an overload of proteostasis systems being associated with pathology in ALS.

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Section: Resultssupporting

confidence: 74%

Section: Resultssupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

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The small heat shock proteins αB-crystallin and Hsp27 suppress SOD1 aggregation in vitro

Yerbury

Gower

Vanags

et al. 2013

Cell Stress and Chaperones

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“…Expression and/or mutation of specific sHSPs are linked to cancer, neurodegenerative diseases, myopathies, and cataract (3,4). Furthermore, sHSPs have been suggested to have therapeutic potential for amyotrophic lateral sclerosis (5) and multiple sclerosis (6), and to positively affect longevity in model organisms (7). Defining the mechanism of sHSP chaperone action, therefore, has wide-ranging implications for understanding cellular stress and disease processes.…”

mentioning

confidence: 99%

Substrate binding site flexibility of the small heat shock protein molecular chaperones

Jaya

García

Vierling

2009

Proc. Natl. Acad. Sci. U.S.A.

217

190

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Small heat shock proteins (sHSPs) serve as a first line of defense against stress-induced cell damage by binding and maintaining denaturing proteins in a folding-competent state. In contrast to the well-defined substrate binding regions of ATP-dependent chaperones, interactions between sHSPs and substrates are poorly understood. Defining substrate-binding sites of sHSPs is key to understanding their cellular functions and to harnessing their aggregation-prevention properties for controlling damage due to stress and disease. We incorporated a photoactivatable cross-linker at 32 positions throughout a well-characterized sHSP, dodecameric PsHsp18.1 from pea, and identified direct interaction sites between sHSPs and substrates. Model substrates firefly luciferase and malate dehydrogenase form strong contacts with multiple residues in the sHSP N-terminal arm, demonstrating the importance of this flexible and evolutionary variable region in substrate binding. Within the conserved ␣-crystallin domain both substrates also bind the ␤-strand (␤7) where mutations in human homologs result in inherited disease. Notably, these binding sites are poorly accessible in the sHSP atomic structure, consistent with major structural rearrangements being required for substrate binding. Detectable differences in the pattern of cross-linking intensity of the two substrates and the fact that substrates make contacts throughout the sHSP indicate that there is not a discrete substrate binding surface. Our results support a model in which the intrinsicallydisordered N-terminal arm can present diverse geometries of interaction sites, which is likely critical for the ability of sHSPs to protect efficiently many different substrates.alpha-crystallin ͉ cross-linking ͉ intrinsic disorder ͉ P-benzoylphenylalanine ͉ protein-protein interactions

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“…In vivo, the overexpression of Hsp27 protected motor neurons from cell death induced by nerve crush [43]. Furthermore, transgenic mice overexpressing Hsp27 and SOD1 G93A showed an improvement in muscle force, reflected by an increase in motor unit numbers and an increase in motor neuron survival in the spinal cord [44]. However, these improvements were only evident at an early stage of the disease and were not sustained over the long term.…”

Section: Alsmentioning

confidence: 99%

Molecular chaperones and neuronal proteostasis

Smith¹,

Li²,

Cheetham³

2015

Seminars in Cell & Developmental Biology

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Protein homeostasis (proteostasis) is essential for maintaining the functionality of the proteome. The disruption of proteostasis, due to genetic mutations or an age-related decline, leads to aberrantly folded proteins that typically lose their function. The accumulation of misfolded and aggregated protein is also cytotoxic and has been implicated in the pathogenesis of neurodegenerative diseases. Neurons have developed an intrinsic protein quality control network, of which molecular chaperones are an essential component. Molecular chaperones function to promote efficient folding and target misfolded proteins for refolding or degradation. Increasing molecular chaperone expression can suppress protein aggregation and toxicity in numerous models of neurodegenerative disease; therefore, molecular chaperones are considered exciting therapeutic targets. Furthermore, mutations in several chaperones cause inherited neurodegenerative diseases. In this review, we focus on the importance of molecular chaperones in neurodegenerative diseases, and discuss the advances in understanding their protective mechanisms.

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Protective effects of heat shock protein 27 in a model of ALS occur in the early stages of disease progression

Cited by 101 publications

References 59 publications

The small heat shock proteins αB-crystallin and Hsp27 suppress SOD1 aggregation in vitro

The small heat shock proteins αB-crystallin and Hsp27 suppress SOD1 aggregation in vitro

Substrate binding site flexibility of the small heat shock protein molecular chaperones

Molecular chaperones and neuronal proteostasis

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