Elevated Alpha-Synuclein Impairs Innate Immune Cell Function and Provides a Potential Peripheral Biomarker for Parkinson's Disease

被引：76

作者：

Gardai, Shyra J. ^{[1
]}

Mao, Wenxian ^{[1
]}

Schuele, Birgitt ^{[2
]}

Babcock, Michael ^{[1
]}

Schoebel, Sue ^{[1
]}

Lorenzana, Carlos ^{[1
]}

Alexander, Jeff ^{[1
]}

Kim, Sam ^{[2
]}

Glick, Heather ^{[1
]}

Hilton, Kathryn ^{[1
]}

Fitzgerald, J. Kent ^{[1
]}

Buttini, Manuel ^{[1
]}

Chiou, San-San ^{[1
]}

McConlogue, Lisa ^{[1
]}

Anderson, John P. ^{[1
]}

Schenk, Dale B. ^{[1
]}

Bard, Frederique ^{[1
]}

Langston, J. William ^{[2
]}

Yednock, Ted ^{[1
]}

Johnston, Jennifer A. ^{[1
]}

机构：

[1] Elan Pharmaceut, Res, San Francisco, CA USA

[2] Parkinsons Inst, Sunnyvale, CA USA

来源：

PLOS ONE | 2013年 / 8卷 / 08期

关键词：

APOPTOTIC CELLS; NEURODEGENERATIVE DISEASES; ARACHIDONIC-ACID; IN-VIVO; PHAGOCYTOSIS; CLEARANCE; MICE; EXPRESSION; EXOCYTOSIS; SECRETION;

D O I：

10.1371/journal.pone.0071634

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Alpha-synuclein protein is strongly implicated in the pathogenesis Parkinson's disease. Increased expression of alpha-synuclein due to genetic multiplication or point mutations leads to early onset disease. While alpha-synuclein is known to modulate membrane vesicle dynamics, it is not clear if this activity is involved in the pathogenic process or if measurable physiological effects of alpha-synuclein over-expression or mutation exist in vivo. Macrophages and microglia isolated from BAC alpha-synuclein transgenic mice, which overexpress alpha-synuclein under regulation of its own promoter, express alpha-synuclein and exhibit impaired cytokine release and phagocytosis. These processes were affected in vivo as well, both in peritoneal macrophages and microglia in the CNS. Extending these findings to humans, we found similar results with monocytes and fibroblasts isolated from idiopathic or familial Parkinson's disease patients compared to age-matched controls. In summary, this paper provides 1) a new animal model to measure alpha-synuclein dysfunction; 2) a cellular system to measure synchronized mobilization of alpha-synuclein and its functional interactions; 3) observations regarding a potential role for innate immune cell function in the development and progression of Parkinson's disease and other human synucleinopathies; 4) putative peripheral biomarkers to study and track these processes in human subjects. While altered neuronal function is a primary issue in PD, the widespread consequence of abnormal alpha-synuclein expression in other cell types, including immune cells, could play an important role in the neurodegenerative progression of PD and other synucleinopathies. Moreover, increased alpha-synuclein and altered phagocytosis may provide a useful biomarker for human PD.

引用

页数：21

共 60 条

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