Immune receptor for pathogenic α-synuclein

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Science  30 Sep 2016:
Vol. 353, Issue 6307, pp. 1498-1499
DOI: 10.1126/science.aai9377

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In neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, specific proteins misfold into β sheet–rich conformations that aggregate. For Parkinson's disease and Lewy body dementia, the hallmark pathology is neuronal inclusions of aggregated α-synuclein called Lewy bodies and Lewy neurites. The spreading of these lesions in the brain is at least partly the result of prionlike self-propagation and cell-to-cell transfer of pathogenic α-synuclein assemblies (1). Inoculation of brain extracts containing aggregated α-synuclein and also synthetic α-synuclein fibrils into mice and nonhuman primates induces aggregation at the injection site, followed by the formation of lesions in neuronally connected brain regions, and ultimately neurodegeneration (2, 3). The appearance of α-synuclein lesions in fetal brain grafts in Parkinson's disease suggests that cell-to-cell spreading of lesions also occurs in humans. There is also in vitro evidence for cell-to-cell transfer of α-synuclein assemblies (2). However, the mechanism of intercellular transmission of α-synuclein aggregates—as well as of other pathogenic protein assemblies, such as those consisting of Aβ and tau in Alzheimer's disease—is poorly understood (1). On page 1513 of this issue, Mao et al. (4) report that the cell-surface lymphocyte activation gene 3 protein (LAG3/CD233) is a neuronal receptor mediating the endocytosis of aggregated α-synuclein, enabling the spread and toxicity of α-synuclein assemblies.