. Structural mechanism of serum amyloid A-mediated inflammatory amyloidosis. Proc Natl Acad Sci U S A. 2014 Apr 8;111(14):5189-94. Epub 2014 Mar 24 PubMed.


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  1. There are some interesting points in the study from the Sun lab that seem to add to general themes found in diseases associated with amyloid aggregation. In all of these diseases, inclusions consisting of an endogenously produced protein mark the progression of the disease. What exactly causes the previously soluble and physiological form of the protein to change conformation into a pathological form and aggregate is in most cases unclear.

    In the case of transthyretin (TTR), a serum protein involved in familial amyloidotic polyneuropathy, a destabilization event induced by either a missense mutation or an external insult leads to depolymerization of the natively tetrameric protein, which then leaves it open to amyloidogenic polymerization (Quintas et al., 1999). The native form, stabilized by its natural ligand thyroxin, is aggregation-resistant. 

    Our lab has recently discovered that a very similar situation can be found for α-synuclein (αS), a mostly neuronally expressed protein of unknown function. This protein is involved in the pathogenesis of Parkinson’s disease and several related disorders through the formation of fibrillar aggregates, so-called Lewy bodies and Lewy neurites. While the monomeric form of αS readily forms fibrils, we have found that the native tetrameric, helically folded form does not undergo this conformational transition without stressors (Bartels et al., 2011; Dettmer et al., 2013). Physiological ligands that stabilize tetrameric αS are not known at the moment, but lipid binding has been reported to inhibit fibril formation for the unfolded monomeric form (Martinez et al., 2007).

    The Sun lab describes several structural features of serum amyloid A (SAA) that seem to resemble the behavior mentioned above. Here again, the native hexameric structure of SAA helps to hide hydrophobic solvent-exposed surfaces present in the monomeric form of the protein, implying that hexamer dissociation is an early pathogenic event. In this study, artificial mutants that destabilize the hexamer result in severe aggregation of SAA, akin to both what has been shown for familial inherited point mutations in TTR (Hurshman Babbes et al., 2008) and what might be the case for genetic variants of αS (Wang et al., 2011). Whether the physiological glycosaminoglycan ligands of SAA stabilize or destabilize the native oligomer or just facilitate its dissociation from high-density lipoprotein, and thereby leave SAA open for subsequent destabilization, unfortunately is not addressed by their study, but would be of great interest for future investigation.

    Furthermore, if destabilization of native assemblies are an early culprit of these different diseases, a general therapeutic strategy based on chemical chaperones (Connelly et al., 2010) mimicking physiologically relevant ligands could become a very attractive approach to treat a plethora of different amyloidoses.


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    . α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature. 2011 Aug 14;477(7362):107-10. PubMed.

    . In vivo cross-linking reveals principally oligomeric forms of α-synuclein and β-synuclein in neurons and non-neural cells. J Biol Chem. 2013 Mar 1;288(9):6371-85. Epub 2013 Jan 14 PubMed.

    . GM1 specifically interacts with alpha-synuclein and inhibits fibrillation. Biochemistry. 2007 Feb 20;46(7):1868-77. PubMed.

    . Quantification of the thermodynamically linked quaternary and tertiary structural stabilities of transthyretin and its disease-associated variants: the relationship between stability and amyloidosis. Biochemistry. 2008 Jul 1;47(26):6969-84. Epub 2008 Jun 7 PubMed.

    . A soluble α-synuclein construct forms a dynamic tetramer. Proc Natl Acad Sci U S A. 2011 Oct 25;108(43):17797-802. Epub 2011 Oct 17 PubMed.

    . Structure-based design of kinetic stabilizers that ameliorate the transthyretin amyloidoses. Curr Opin Struct Biol. 2010 Feb;20(1):54-62. PubMed.

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