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Extracellular α-synuclein—a novel and crucial factor in Lewy body diseases

Nature Reviews Neurology volume 10, pages 92–98 (2014)Cite this article

Subjects

Key Points

  • Neurons secrete monomeric and oligomeric α-synuclein through unconventional exocytosis

  • Extracellular α-synuclein is taken up by neurons and glia through endocytosis and undergoes endocytic trafficking for degradation in lysosomes

  • α-Synuclein aggregates can be transmitted from neuron to neuron via the extracellular milieu and can propagate aggregates by a 'seeding' mechanism

  • Extracellular α-synuclein oligomers activate microglia via activation of Toll-like receptor 2

  • Targeting of extracellular α-synuclein—for example, promoting its clearance—might be a promising therapeutic strategy for modifying the progression of Lewy body diseases

Abstract

Misfolding and intracellular aggregation of α-synuclein are thought to be crucial factors in the pathogenesis of Lewy body diseases (LBDs), such as Parkinson disease. However, the pathogenic modifications of this protein and the mechanisms underlying its activity have not been fully characterized. Recent studies suggest that small amounts of α-synuclein are released from neuronal cells by unconventional exocytosis, and that this extracellular α-synuclein contributes to the major pathological features of LBD, such as neurodegeneration, progressive spreading of α-synuclein pathology, and neuroinflammation. In this article, we review a rapidly growing body of literature on possible mechanisms by which extracellular α-synuclein contributes to LBD pathology, and discuss therapeutic approaches to target this form of α-synuclein to halt disease progression.

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Figure 1: Potential pathways for exogenous 'seeds' to meet endogenous α-synuclein.
Figure 2: Physiological processing and pathogenic dysregulation of α-synuclein—a working model.
Figure 3: Potential therapeutic strategies to target pathogenic extracellular α-synuclein.

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Acknowledgements

This work was supported by a National Research Foundation grant, funded by the Korean Government (2010-0015,188), and by the Korea Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A111228).

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Authors and Affiliations

  1. Department of Anatomy, School of Medicine, Konkuk University, 120 Neungdong-ro, Seoul, 143-701, Gwangjin-gu, Korea

    He-Jin Lee

  2. Department of Biomedical Science and Technology, Konkuk University, 120 Neungdong-ro, Seoul, 143-701, Gwangjin-gu, Korea

    Eun-Jin Bae & Seung-Jae Lee

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S.-J. Lee researched data for the article. All authors made substantial contributions to discussion of the content, writing of the article, and to review and/or editing of the manuscript before submission.

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Correspondence to Seung-Jae Lee.

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Lee, HJ., Bae, EJ. & Lee, SJ. Extracellular α-synuclein—a novel and crucial factor in Lewy body diseases. Nat Rev Neurol 10, 92–98 (2014). https://doi.org/10.1038/nrneurol.2013.275

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