Trends in Molecular Medicine

Trends in Molecular Medicine

Volume 7, Issue 9, 1 September 2001, Pages 414-421
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Review
Unfolding retinal dystrophies: a role for molecular chaperones?

https://doi.org/10.1016/S1471-4914(01)02103-7Get rights and content

Abstract

Inherited retinal dystrophy is a major cause of blindness worldwide. Recent molecular studies have suggested that protein folding and molecular chaperones might play a major role in the pathogenesis of these degenerations. Incorrect protein folding could be a common consequence of causative mutations in retinal degeneration disease genes, particularly mutations in the visual pigment rhodopsin. Furthermore, several retinal degeneration disease genes have recently been identified as putative facilitators of correct protein folding, molecular chaperones, on the basis of sequence homology. We also consider whether manipulation of chaperone levels or chaperone function might offer potential novel therapies for retinal degeneration.

Section snippets

Protein misfolding and retinal disease

Correct protein folding is an essential biological process. To ensure this happens in the intracellular milieu many proteins interact with molecular chaperones (Box 2). The importance of correct protein folding and the potential involvement of molecular chaperones in retinal degeneration are emphasized by the most common and studied form of inherited retinal degeneration, retinitis pigmentosa (RP) caused by mutations in rhodopsin – the molecular sensor for light.

RP2 and RP

Mutations in RP2 account for 15–20% of X-linked retinitis pigmentosa (XLRP) 16. RP2 was identified as a putative chaperone on the basis of its similarity (30.4% identity over 151 amino acids) to cofactor C, a component of the tubulin folding pathway 17, 18. The significance of this similarity is supported by pathogenic amino-acid substitutions in RP2 at conserved residues 16, 19, 20, suggesting that RP2 has functional homology with cofactor C.

Molecular chaperones, in particular the cytosolic

The therapeutic potential of manipulating molecular chaperones in retinal degeneration

The upregulation of many molecular chaperones as part of the cellular response to stress is one of their characteristic features, and led to their initial identification as heat shock proteins (Fig. 2f). This is not only a reactive but also an adaptive response and can protect the cell against future stress, a phenomenon known as thermotolerance. Even before the identification of the first rhodopsin mutations, it had been demonstrated that thermotolerance could be exploited to protect the

Outstanding questions

  • •

    How does the misfolding of rhodopsin lead to photoreceptor cell death by apoptosis?

  • •

    Does the retina contain specialized molecular chaperone machines and what are their client proteins?

  • •

    Can molecular chaperone manipulation be used as a general treatment for misfolded proteins in retinal degeneration; in particular, can the folding of rhodopsin be manipulated to improve photoreceptor survival (by molecular chaperones or ligand, such as vitamin A)?

  • •

    Can the anti-apoptotic effects of molecular

Acknowledgements

We wish to thank AndrewWebster, BartLeroy and Alan Bird for fundus photographs and The Wellcome Trust, BBSRC and Fight for Sight for funding.

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