Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies.

Abstract

Abnormal neuronal aggregation of alpha-synuclein is implicated in the development of many neurological disorders, including Parkinson disease and dementia with Lewy bodies. Glial cells also show extensive alpha-synuclein pathology and may contribute to disease progression. However, the mechanism that produces the glial alpha-synuclein pathology and the interaction between neurons and glia in the disease-inflicted microenvironment remain unknown. Here, we show that alpha-synuclein proteins released from neuronal cells are taken up by astrocytes through endocytosis and form inclusion bodies. The glial accumulation of alpha-synuclein through the transmission of the neuronal protein was also demonstrated in a transgenic mouse model expressing human alpha-synuclein. Furthermore, astrocytes that were exposed to neuronal alpha-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 alpha-synuclein. Together, these results suggest that astroglial alpha-synuclein pathology is produced by direct transmission of neuronal alpha-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.

• Authors: He-Jin Lee, Ji-Eun Suk, Christina Patrick, Eun-Jin Bae, Ji-Hoon Cho, Sangchul Rho, Daehee Hwang, Eliezer Masliah, Seung-Jae Lee
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 12 Pg. 9262-72 (Mar 19 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20071342 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Culture Media, Conditioned
• alpha-Synuclein

Topics

• Animals
• Astrocytes (metabolism)
• Cell Differentiation
• Cell Line, Tumor
• Culture Media, Conditioned (pharmacology)
• Humans
• Inflammation
• Male
• Mice
• Mice, Transgenic
• Models, Biological
• Neurodegenerative Diseases (metabolism)
• Neurons (metabolism)
• Rats
• Rats, Sprague-Dawley
• alpha-Synuclein (metabolism)