Guo JL, Covell DJ, Daniels JP, Iba M, Stieber A, Zhang B, Riddle DM, Kwong LK, Xu Y, Trojanowski JQ, Lee VM.
Distinct α-synuclein strains differentially promote tau inclusions in neurons.
Cell. 2013 Jul 3;154(1):103-17.
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The concept of "strains" emanates from the prion field. It has been shown both in vitro and in animal models that the disease-associated prion protein (PrPsc) can exhibit differences in misfolding and aggregation. These different forms tend to be stable and can be propagated, again both in vitro and in vivo. The mechanism for propagation is "seeding," during which preformed aggregates with a high degree of β-sheet structure interact with normal protein and thereby transfer the folding and aggregation abnormality. The process is poorly understood. The prion strains are believed to cause different disease phenotypes. For example, variant Creutzfeldt-Jakob disease, characterized by prion variants with a typical protease K resistance pattern, are discernible from PrPsc in other prion disorders.
In this article, Guo et al. show that recombinant α-synuclein can adopt at least two fibrillar conformations, called A and B. These conformations are shown to propagate in vitro and induce different conformations in cellular systems. The most interesting and novel finding is that strain B is able to induce misfolding and aggregation of tau, the protein that makes up the neurofibrillary tangles seen in several different cerebral disorders, including Alzheimer’s and Parkinson’s diseases. This type of interaction between two proteins is called cross-seeding. Interestingly, strain B, but not strain A α-synuclein fibrils, induces tau aggregation in a transgenic mouse model by cross-seeding as well. The authors conclude there may exist many distinct fibril conformations with different abilities to cross-seed, leading to variations in forms of aggregates and that this may be a reason for differences in disease phenotypes in Parkinson's. A notable and potentially important detail is that while strain A is toxic, strain B is not. This finding shows that aggregates may be deleterious in ways other than just exerting toxicity.
The paper is interesting and the experiments very well-performed, increasing our knowledge of how proteins making up cerebral aggregates interact with each other. However, the authors ignore studies of other amyloid fibril proteins that cross-seed outside of the brain. Seeding and cross-seeding are mechanism shown with other amyloid fibril proteins, in both localized and systemic diseases, and cross-seeding has been shown to occur in animal models of systemic amyloidoses caused by amyloid A and apolipoprotein AII. In addition, and contrary to what Guo et al. state at the end of their discussion, the strain phenomenon has been proposed for peripheral amyloid diseases due to amyloid A and transthyretin. It is, therefore, very conceivable that strain formation and cross-seeding are mechanisms of general importance in many or all amyloid diseases. This is a field that deserves much more attention.
This work demonstrates the existence of assembled α-synuclein strains, based on the cross-seeding (or not) of tau aggregation. This is important for understanding some human neurodegenerative diseases, where α-synuclein inclusions are present in different cell types and different parts of the nervous system, sometimes in conjunction with tau inclusions. Aggregates of tau give rise to distinct human tauopathies and recent experiments have shown that strains of assembled four-repeat tau appear to exist (Clavaguera et al., 2013). Strains of assembled α-synuclein and tau provide a further link with prion diseases, where different aggregate conformations of the prion protein give rise to distinct disease phenotypes and neuropathologies.
Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S, Hench J, Probst A, Winkler DT, Reichwald J, Staufenbiel M, Ghetti B, Goedert M, Tolnay M.
Brain homogenates from human tauopathies induce tau inclusions in mouse brain.
Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9535-40.