Roles of molecular chaperones in protein misfolding diseases

doi:10.1016/j.semcdb.2003.12.010

Seminars in Cell & Developmental Biology

Volume 15, Issue 1, February 2004, Pages 17-29

https://doi.org/10.1016/j.semcdb.2003.12.010 Get rights and content

Abstract

Human misfolding diseases result from the failure of proteins to reach their active state or from the accumulation of aberrantly folded proteins. The mechanisms by which molecular chaperones influence the development of these diseases is beginning to be understood. Mutations that compromise the activity of chaperones lead to several rare syndromes. In contrast, the more frequent amyloid-related neurodegenerative diseases are caused by a gain of toxic function of misfolded proteins. Toxicity in these disorders may result from an imbalance between normal chaperone capacity and production of dangerous protein species. Increased chaperone expression can suppress the neurotoxicity of these molecules, suggesting possible therapeutic strategies.

Introduction

Proteins are central to all biological processes. To become functionally active, newly synthesized protein chains must fold into unique three-dimensional conformations, based on the information encoded in their amino acid sequences. Although in vitro many proteins can fold to their native state spontaneously without the aid of additional components, in vivo a group of proteins, collectively known as molecular chaperones, are essential for protein folding to occur with high efficiency. The main role of these components is to prevent protein misfolding and aggregation, off-pathway reactions that would otherwise limit the folding yield under cellular conditions.

In recent years, the process of protein folding has been recognized to be of considerable medical relevance. Indeed, a number of human diseases are now known to result, directly or indirectly, from aberrant folding reactions (Table 1). Classic examples include Alzheimer’s disease, cystic fibrosis and hypertrophic cardiomyopathy, to mention only a few. There are various mechanisms by which the accumulation of misfolded protein chains may cause cellular dysfunction, and often a combination of these appears to be responsible for the disease. Misfolded polypeptides not only loose their normal function, they may also form toxic species, including oligomers or larger aggregates (e.g. amyloid precursor protein (APP) in Alzheimer’s and other neurodegenerative diseases), they may be prevented from reaching their proper cellular localization due to retention and/or degradation (e.g. CFTR in cystic fibrosis), or they may exert a dominant negative effect by preventing the function of interacting partners (e.g. myosin in hypertrophic cardiomyopathy).

Recently, a more direct involvement of molecular chaperones in human diseases of protein folding has become increasingly evident. Here, we will review the experimental evidence for such a connection. We will begin by examining our current understanding of the mechanisms by which molecular chaperones prevent misfolding and aggregation of their substrate proteins. Then, we will survey an expanding group of diseases caused by mutations in actual or putative chaperone proteins. Finally, we will explore the mechanisms by which the normal functions of chaperones may influence the development of disease states associated with protein aggregation.

Section snippets

Molecular chaperones prevent protein misfolding and aggregation

Within the concentrated milieu of the cell, proteins encounter particular challenges during the acquisition and maintenance of their functional states. The properties of the peptide bond confer a high degree of conformational flexibility to the protein backbone, while the amino acid side chains allow a large number of mostly non-covalent interactions. Thus, the protein chain can theoretically adopt an enormous number of different conformations, and generally only one of these corresponds to its

Mutations in molecular chaperones as the cause of human disease

The identification of mutations responsible for a wide variety of inherited human diseases has been greatly accelerated in recent years, due to the availability of detailed genetic mapping tools developed in the large-scale genome sequencing projects. Interestingly, analysis of the open reading frames (ORFs) harboring these mutations has revealed that alterations in genes encoding molecular chaperones with well-established functions may indeed be responsible for some human diseases with complex

Role of normal chaperone functions in aggregation diseases

While the diseases described above appear to be caused by the loss of function of various chaperone substrate proteins, a hallmark of an important group of neurodegenerative diseases is the formation of brain lesions associated with the intra- or extracellular deposition of amyloid-like protein aggregates (see article by Hirschfield in press and [76], [77]). These disorders are thought to result from the acquisition of dominant, toxic functions by aberrantly folded proteins, often due to

Conclusions

Molecular chaperones play fundamental roles in the biogenesis of a diverse set of proteins in the cell. An increasing body of evidence now links both the normal functions of chaperones as well as the loss of chaperone function to the mechanisms of important human diseases. While it is unlikely that mutations leading to a complete loss of function of a general chaperone will be identified as responsible for human disease, several reports have identified mutations in specialized chaperones as the

Acknowledgements

J.M.B. is supported by a Human Frontiers Science Program fellowship. S.A.B. is funded by a fellowship from the Hereditary Disease Foundation.

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Chaperones are bind and aid numerous proteins under specific physiological and pathological, however if a protein fails to fold appropriately, despite the support of a chaperones, the chaperone becomes stuck on the protein. This causes the induction of second messengers or molecular inducers that promote the expression of further chaperone proteins or favor the degradation of defective proteins (Barral et al., 2004; Hetz, 2012; Hetz & Glimcher, 2011). Molecular chaperones include, among others, heat shock proteins (HSP), a group of proteins activated by heat shock mainly characterized by HSP70, HSP90, DNAJ/HSP40, chaperonin/HSP60, and by the small HSP (sHSP) families (Barral et al., 2004).
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Roles of molecular chaperones in protein misfolding diseases

Abstract

Introduction

Section snippets

Molecular chaperones prevent protein misfolding and aggregation

Mutations in molecular chaperones as the cause of human disease

Role of normal chaperone functions in aggregation diseases

Conclusions

Acknowledgements

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Embo. J.

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Science

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Embo. J.

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

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Nat. Cell Biol.