Oncotarget

Research Papers: Gerotarget (Focus on Aging):

Age- and brain region-dependent α-synuclein oligomerization is attributed to alterations in intrinsic enzymes regulating α-synuclein phosphorylation in aging monkey brains

Min Chen, Weiwei Yang, Xin Li, Xuran Li, Peng Wang, Feng Yue, Hui Yang, Piu Chan and Shun Yu _

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Oncotarget. 2016; 7:8466-8480. https://doi.org/10.18632/oncotarget.6445

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Abstract

Min Chen1,2, Weiwei Yang1,2, Xin Li1,2, Xuran Li1,2, Peng Wang1,2, Feng Yue1,2, Hui Yang2,3, Piu Chan1,2,3 and Shun Yu1,2,3

1 Department of Neurobiology, Xuanwu Hospital of Capital Medical University, Beijing, China

2 Center of Parkinson’s Disease, Beijing Institute for Brain Disorders, Beijing, China

3 Beijing Key Laboratory for Parkinson’s Disease, Beijing, China

Correspondence to:

Shun Yu, email:

Keywords: α-synuclein, polo-like kinase 2, protein phosphatase 2A, aging, brain, Gerotarget

Received: August 03, 2015 Accepted: November 16, 2015 Published: December 01, 2015

Abstract

We previously reported that the levels of α-syn oligomers, which play pivotal pathogenic roles in age-related Parkinson’s disease (PD) and dementia with Lewy bodies, increase heterogeneously in the aging brain. Here, we show that exogenous α-syn incubated with brain extracts from older cynomolgus monkeys and in Lewy body pathology (LBP)-susceptible brain regions (striatum and hippocampus) forms higher amounts of phosphorylated and oligomeric α-syn than that in extracts from younger monkeys and LBP-insusceptible brain regions (cerebellum and occipital cortex). The increased α-syn phosphorylation and oligomerization in the brain extracts from older monkeys and in LBP-susceptible brain regions were associated with higher levels of polo-like kinase 2 (PLK2), an enzyme promoting α-syn phosphorylation, and lower activity of protein phosphatase 2A (PP2A), an enzyme inhibiting α-syn phosphorylation, in these brain extracts. Further, the extent of the age- and brain-dependent increase in α-syn phosphorylation and oligomerization was reduced by inhibition of PLK2 and activation of PP2A. Inversely, phosphorylated α-syn oligomers reduced the activity of PP2A and showed potent cytotoxicity. In addition, the activity of GCase and the levels of ceramide, a product of GCase shown to activate PP2A, were lower in brain extracts from older monkeys and in LBP-susceptible brain regions. Our results suggest a role for altered intrinsic metabolic enzymes in age- and brain region-dependent α-syn oligomerization in aging brains.


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