Direct Transfer of α-Synuclein from Neuron to Astroglia Causes Inflammatory Responses in Synucleinopathies*
By He‐Jin Lee, Ji-Eun Suk, C. Patrick, Eun-Jin Bae, Ji-Hoon Cho, Sangchul Rho, D. Hwang, E. Masliah, Seung-Jae Lee. Journal of Biological Chemistry, 2010
775 citations recorded by the source corpus.
Abnormal neuronal aggregation of α-synuclein is implicated in the development of many neurological disorders, including Parkinson disease and dementia with Lewy bodies. Glial cells also show extensive α-synuclein pathology and may contribute to disease progression. However, the mechanism that produces the glial α-synuclein pathology and the interaction between neurons and glia in the disease-inflicted microenvironment remain unknown. Here, we show that α-synuclein proteins released from neuronal cells are taken up by astrocytes through endocytosis and form inclusion bodies. The glial accumulation of α-synuclein through the transmission of the neuronal protein was also demonstrated in a transgenic mouse model expressing human α-synuclein. Furthermore, astrocytes that were exposed to neuronal α-synuclein underwent changes in the gene expression profile reflecting an inflammatory response. Induction of pro-inflammatory cytokines and chemokines correlated with the extent of glial accumulation of α-synuclein. Together, these results suggest that astroglial α-synuclein pathology is produced by direct transmission of neuronal α-synuclein aggregates, causing inflammatory responses. This transmission step is thus an important mediator of pathogenic glial responses and could qualify as a new therapeutic target.
Subfields: Cellular and Molecular Neuroscience, Neurology, Physiology
View Paper: https://www.semanticscholar.org/paper/ce1b3e1bb5fdd5a535f9824247403488d1753b2e
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Citations in the corpus
- α-Synuclein in Parkinson's disease. (2012, background): “Furthermore, various reports have shown that extracellular a-synuclein can induce inflammatory reactions in glial cells, thus further potentiating neurodegeneration (Zhang et al. 2005; Klegeris et al. 2008; Lee et al. 2010).”
- Toll-like receptor 4 is required for α-synuclein dependent activation of microglia and astroglia (2013, methodology): “The amount of endotoxin in the stock solutions was under 1 EU/mg, i.e., a concentration that is incapable of inducing significant glial activation as previously reported (Gao et al., 2003; Lee et al., 2010a; Park et al., 2008; Zhang et al., 2005).”
- Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats (2014, background): “Further experimental studies have shown that Lewy pathology can indeed propagate from one cell to another, not only in cultured cells in vitro, but also in brains of animal models of PD [11, 15, 27, 33].”