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J Mol Neurosci. 2008;34(1):17-22. Epub 2007 Apr 17.

Origins and effects of extracellular alpha-synuclein: implications in Parkinson's disease.

Author information

1
Center for Geriatric Neuroscience Research, Institute of Biomedical Science and Technology, Department of Biomedical Science and Technology, Konkuk University, Seoul, Republic of Korea. sjlee@konkuk.ac.kr

Abstract

Misfolding and abnormal aggregation of the neuronal protein alpha-synuclein has been implicated in the pathogenesis of Parkinson's disease and related neurological disorders, such as dementia with Lewy bodies. alpha-synuclein is a conventional cytosolic protein and is thought to exert its pathogenic function exclusively in the neuronal cytoplasm in a cell-autonomous manner. However, the current model is being challenged by a series of new observations that demonstrate the presence of alpha-synuclein and its aggregated forms in the extracellular fluid both in vivo and in vitro. Extracellular alpha-synuclein appears to be delivered by unconventional exocytosis of intravesicular alpha-synuclein, although the exact mechanism has not been characterized. Compared to the cytosolic alpha-synuclein, intravesicular alpha-synuclein is prone to aggregation and the potential source of extracellular aggregates. A number of tissue culture studies suggest that exposure to extracellular alpha-synuclein aggregates induces microglial activation, release of pro-inflammatory cytokines from astrocytes, and neurotoxicity. Thus, exocytosis of alpha-synuclein may be an important mechanism for amplifying and spreading degenerative changes from a small group of cells to its surrounding tissues, and it potentially provides therapeutic targets for halting the progression of the disease.

PMID:
18157654
DOI:
10.1007/s12031-007-0012-9
[Indexed for MEDLINE]

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