. α-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature. 2015 Jun 18;522(7556):340-4. Epub 2015 Jun 10 PubMed.

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  1. α-Synuclein aggregates: Different strains for different pathologies?

    Synucleinopathies are progressive neurodegenerative diseases with the presence of protein inclusions in brain cells, where the predominant component is α-synuclein. They comprise, among others, Parkinson’s disease, multisystem atrophy, and pure autonomic failure, which can be distinguished from one another neuropathologically by the localization of α-synuclein inclusions in different shapes, in different cell types, and in different anatomical locations in the brain. Mechanisms underlying the tremendous clinical and neuropathological heterogeneity of synucleinopathies remain unclear.

    The discovery that fibrils formed of recombinant α-synuclein could spread to previously healthy neurons and act as seeds in cells to induce the recruitment of soluble endogenous α-synuclein into insoluble pathologic aggregates (Luk et al., 2009) paved the way for numerous subsequent studies that investigated the seeding and spreading capacity of different α-synuclein preparations in different experimental settings (Desplats et al., 2009; Hansen et al., 2011).

    In this study published recently in Nature, Peelaerts et al. propose that the differences between distinct synucleinopathies may be caused by different "strains" of α-synuclein (Peelaerts et al., 2015). 

    The notion of α-synuclein strains has been proposed previously by several groups. They have been conceptualized as conformational variants of α-synuclein with different seeding properties in cellular and organismal contexts (Guo et al., 2015). Furthermore, it has been previously shown that different strains of α-synuclein, namely ultrastructurally defined fibrils and ribbons, can be obtained in vitro by applying different oligomerization conditions. These strains showed differences in size, structure, toxicity, lipid-binding potential, and seeding potential in a cell model (Bousset et al., 2013).

    Following up on these findings, Peelaerts et al. investigated whether these strains caused different biological changes and pathologies in rats. The in vivo properties of fluorescently labeled α-synuclein oligomers and two distinct strains, fibrils and ribbons, were compared by inoculation into the rat substantia nigra in the absence or presence of α-synuclein overexpression. In this experimental setting, oligomers and ribbons showed more spreading potential than fibrils, but only ribbons were able to cause large deposits of phosphorylated α-synuclein that shared properties with Lewy bodies and Lewy neurites defining Parkinson’s disease. On the other hand, fibrils had the most pronounced neurotoxic effects and were able to induce neurodegeneration of dopaminergic neurons with a motor deficient phenotype. These findings are consistent with previous studies in mice (Luk et al., 2012; Masuda-Suzukake et al., 2014). More strikingly, the injection of ribbons in a system where α-synuclein is overexpressed led to the appearance of phosphorylated α-synuclein deposits in oligodendroglial cells, whereas fibrils caused depositions only in neurons. Whether these deposits share common properties with the glial cytoplasmic inclusions defining multisystem atrophy is not clear, but this finding supports the hypothesis that different strains acting under different conditions cause different pathologies.

    Moreover, the proteinase K resistance of α-synuclein aggregates extracted from brains, which have been inoculated with either fibrils or ribbons, was different. This may imply that the different strains act as seeds and have the ability to imprint endogenous α-synuclein with their respective structures.

    This study also shows that systemic administration of α-synuclein strains leads to deposition in the brain, consistent with previous findings where intramuscular and gastric injections of α-synuclein assemblies led to deposition and pathology in the brain (Holmqvist et al., 2012; Sacino et al., 2014). This implies that α-synuclein pathology can be initiated in a peripheral system and then spread to the brain, where it causes neuronal dysfunctions. This clinically relevant issue needs to be further investigated.

    These findings  shed light on several questions relating to the implications of α-synuclein in different pathologies. The concept of strains seems to be of utmost relevance when it comes to explaining the molecular basis defining distinct synucleinopathies. Fibrils are reported to be the primary culprit for neurodegeneration and behavioral and motor deficits, whereas ribbons seem to be associated with the formation of Lewy bodies and deposits in glial cells, but do not appear to be involved in toxicity. On the other hand, oligomers seem to spread faster and more efficiently than fibrils and ribbons. Oligomers were also able to affect the synaptic transmission to the same extent as fibrils, but surprisingly, contrary to studies that have reported toxicity induced by α-synuclein oligomers (Luth et al., 2014), they did not show any toxic or seeding effects in this model. This could be explained with their faster removal by clearance pathways due to their smaller size, but the toxic potential of oligomers nonetheless needs to be characterized and studied in more detail.

    More importantly, this work opens up several questions. Do these strains exist in synucleinopathies in human patients? And how can this issue be addressed? Moreover, in synucleinopathies, both α-synuclein-rich inclusions and cell toxicity are occurring. If it is assumed that ribbons are responsible for depositions and fibrils are responsible for toxicity, then these strains must co-exist in the same diseased system. Do strains collaborate in a fashion that induces a differential pathological process leading to different synucleinopathies? Or is the difference caused by different proportions of strains, which would be induced by different microenvironments of cells? And what role does the genetic background play on the formation of different strains? All these questions need to be investigated in order to have a clearer view of how the heterogeneity of synucleinopathies is generated.

    Despite the fact that several groups report that fibrils are the α-synuclein strain responsible for neurodegeneration, an important question needs to be addressed jointly by the field to clarify what defines biologically active fibrils: Different groups utilize different α-synuclein preparations with in vitro oligomerization conducted under different conditions to make fibrils. This raises the question of how to improve the reproducibility of experiments done with α-synuclein strains or seeds. There seems to be a great need to standardize protocols and nomenclature to be able to compare observations across different studies.

    References:

    . Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20051-6. PubMed.

    . Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):13010-5. PubMed.

    . α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest. 2011 Feb 1;121(2):715-25. PubMed.

    . α-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature. 2015 Jun 18;522(7556):340-4. Epub 2015 Jun 10 PubMed.

    . Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell. 2013 Jul 3;154(1):103-17. PubMed.

    . Structural and functional characterization of two alpha-synuclein strains. Nat Commun. 2013;4:2575. PubMed.

    . Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science. 2012 Nov 16;338(6109):949-53. PubMed.

    . Pathological alpha-synuclein propagates through neural networks. Acta Neuropathol Commun. 2014 Aug 6;2:88. PubMed.

    . Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 2014 Dec;128(6):805-20. Epub 2014 Oct 9 PubMed.

    . Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice. Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10732-7. Epub 2014 Jul 7 PubMed.

    . Soluble, prefibrillar α-synuclein oligomers promote complex I-dependent, Ca2+-induced mitochondrial dysfunction. J Biol Chem. 2014 Aug 1;289(31):21490-507. Epub 2014 Jun 18 PubMed.

    View all comments by Guenter Hoeglinger

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