Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets

Han, May; Hwang, Sun-Il; Roy, Dolly B.; Lundgren, Deborah H.; Price, J. M.; Ousman, Shalina S.; Fernald, Guy Haskin; Gerlitz, Bruce; Robinson, William H.; Baranzini, Sergio E.; Grinnell, Brian W.; Raine, Cedric S.; Sobel, Raymond A.; Han, David K.; Steinman, Lawrence

doi:10.1038/nature06559

Cited by 477 publications

(555 citation statements)

References 36 publications

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“…It has been shown that Bc is the most prominent protein present in plaques of MS patients [198] and the CRYAB gene is the most highly induced in plaque tissue compared to normal tissue [199]. The increased expression of Bc, along with other Hsps, is proposed to be part of the oligodendrocyte's survival response [180].…”

Section: Viral Infection) Patients With Ms Have Numerous Demyelinatementioning

confidence: 99%

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

Treweek

Meehan

Ecroyd

et al. 2014

Cell. Mol. Life Sci.

180

177

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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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Section: Viral Infection) Patients With Ms Have Numerous Demyelinatementioning

confidence: 99%

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

Treweek

Meehan

Ecroyd

et al. 2014

Cell. Mol. Life Sci.

180

177

View full text Add to dashboard Cite

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“…in addition to the traditional staining of brain sections, modern molecular techniques are being used to study the contents of the MS lesions. Despite concerns about how tissues are preserved for this purpose and the caveat that post-mortem tissues may reflect only the endgame rather the ongoing disease process, some limited initial transcriptomic and 2D-mass spectrometry proteomic profiling data have been reported [79] . A cursory examination of the data reveals an enrichment of proteins important for material transport, structural integrity and adhesion.…”

Section: Challengesmentioning

confidence: 99%

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

Zhang

Guo

2013

Neurosci. Bull.

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Multiple sclerosis (MS) is a chronic and devastating autoimmune demyelinating disease of the central nervous system. With the increased understanding of the pathophysiology of this disease in the past two decades, many disease-modifying therapies that primarily target adaptive immunity have been shown to prevent exacerbations and new lesions in patients with relapsing-remitting MS. However, these therapies only have limited efficacy on the progression of disability. Increasing evidence has pointed to innate immunity, axonal damage and neuronal loss as important contributors to disease progression. Remyelination of denuded axons is considered an effective way to protect neurons from damage and to restore neuronal function. The identification of several key molecules and pathways controlling the differentiation of oligodendrocyte progenitor cells and myelination has yielded clues for the development of drug candidates that directly target remyelination and neuroprotection. The long-term efficacy of this strategy remains to be evaluated in clinical trials. Here, we provide an overview of current and emerging therapeutic concepts, with a focus on the opportunities and challenges for the remyelination approach to the treatment of MS.

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“…However, much work is yet to be done to achieve a comprehensive understanding of molecular logic underlying optimal remyelination. In this regard, genomic [77], gene expression [78] and proteomic [79] analyses of MS patients will be critical.…”

Section: Conclusion and Future Prospectsmentioning

confidence: 99%

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

et al. 2011

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Regeneration of myelin sheaths (remyelination) after central nervous system demyelination is important to restore saltatory conduction and to prevent axonal loss. In multiple sclerosis, the insufficiency of remyelination leads to the irreversible degeneration of axons and correlated clinical decline. Therefore, a regenerative strategy to encourage remyelination may protect axons and improve symptoms in multiple sclerosis. We highlight recent studies on factors that influence endogenous remyelination and potential promising pharmacological targets that may be considered for enhancing central nervous system remyelination.

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Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets

Cited by 477 publications

References 36 publications

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

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

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

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