Les amyloses, un modèle de maladie du repliement des protéines

Abstract

Longtemps considérée comme une maladie unique, l’amylose est aujourd’hui reconnue comme la marque histologique d’un ensemble de maladies, les amyloses. L’amylose est la voie finale commune, chez l’homme et dans de nombreuses espèces animales, de l’agrégation pathologique de plus de vingt protéines appartenant à des familles dénuées de relation fonctionnelle ou structurale. Les mécanismes de formation de ces agrégats commencent à être mieux connus. L’étape centrale, que l’on peut artificiellement reproduire in vitro, est un changement de conformation d’une protéine native en une protéine apte à l’auto-agrégation, sous une forme essentiellement formée de feuillets β. Le traitement actuel des amyloses, qui consiste à réduire la disponibilité en protéine amyloïde, n’est pas pleinement satisfaisant. La reconnaissance progressive des différentes étapes de ce phénomène pathologique a conduit à la conception de cibles thérapeutiques nouvelles : stabilisation de la protéine native, désagrégation des structures déjà β-plissées ou, encore, inhibition des liaisons avec certains composants du tissu conjonctif. Différentes approches, pharmacologiques et immunologiques, sont à l’étude sur des systèmes cellulaires et des modèles animaux, et certaines molécules sont parvenues au stade de l’essai clinique chez l’homme.

Amyloidosis bears many characteristics of orphan diseases. Its diagnosis is difficult and often delayed. The main reasons thereof are its quite various clinical presentation: amyloidosis behaves as a new great masquerader, and the need to get a tissue sample to submit to specific dyes. Although we have been able for a long time to recognize amyloid, its intimate nature has remained quite completely enigmatic until recently. In fact, major advances in this way have appeared only in the last decade and it is now possible to consider the mechanisms of amyloidosis as a multistep phenomenon. Amyloidosis is no more thought only as a « storage disease » of the extracellular space. This archaic viewpoint has shifted to the emerging paradigm of misfolded protein disorders. Amyloid proteins thus appear as a subgroup of misfolded proteins, where misfolding leads to subsequent aggregation. This aggregation may be a generic property of polypeptide chains possibly linked to their common peptide backbone that does not depend on specific amino acid sequences. And, in fact, many proteins can in vitro form amyloid- like aggregates, while in vivo, only 20 amyloid proteins have been so far identified. Although misfolding and aggregation are quite well studied in vitro, the last step of amyloid deposition, i.e. anchorage to the extracellular matrix, can not be so easily approached. Proteoglycans and serum amyloid P component have nevertheless been identified as key elements involved in extracellular deposition of amyloid proteins. These advances have opened new avenues in the therapeutic of amyloid disorders. Current treatment consists of support or replacement of impaired organ function and measures to reduce the production of amyloidogenic precursor proteins. Potential novel therapeutic strategies include stabilisation of the native fold of precursor proteins with targeted small molecules, reversion of misfolded proteins to their native state with « betasheet breakers », inhibition of amyloid fibril propagation and enhancement of amyloid clearance either through immunotherapy or by reducing the stability of deposits through depletion of serum amyloid P component, and breaking the anchorage to the extracellular matrix with glycosaminoglycan analogs.