title: Age- and brain region-dependent α-synuclein oligomerization is attributed to alterations in intrinsic enzymes regulating α-synuclein phosphorylation in aging monkey brains.
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.
authors.affiliation: Department of Neurobiology, Xuanwu Hospital of Capital Medical University, Beijing, China.|Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Neurobiology, Xuanwu Hospital of Capital Medical University, Beijing, China.|Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Neurobiology, Xuanwu Hospital of Capital Medical University, Beijing, China.|Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Neurobiology, Xuanwu Hospital of Capital Medical University, Beijing, China.|Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China.
authors.forename: Xuran
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Neurobiology, Xuanwu Hospital of Capital Medical University, Beijing, China.|Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Xuanwu Hospital of Capital Medical University, Beijing, China.|Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Yue
authors.affiliation: Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China.|Beijing Key Laboratory for Parkinson's Disease, Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Neurobiology, Xuanwu Hospital of Capital Medical University, Beijing, China.|Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China.|Beijing Key Laboratory for Parkinson's Disease, Beijing, China.
authors.forename: Piu
authors.initials: P
authors.lastname: Chan
authors.affiliation: Department of Neurobiology, Xuanwu Hospital of Capital Medical University, Beijing, China.|Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China.|Beijing Key Laboratory for Parkinson's Disease, Beijing, China.
authors.forename: Shun
authors.initials: S
authors.lastname: Yu
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D049109:Cell Proliferation; D002518:Ceramides / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D005962:Glucosylceramidase / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D016631:Lewy Bodies / Q000378:metabolism / Q000473:pathology; D008252:Macaca fascicularis; D010766:Phosphorylation; D055503:Protein Multimerization; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D002518:Ceramides; D051844:alpha-Synuclein; D017346:Protein Serine-Threonine Kinases; D054648:Protein Phosphatase 2; D005962:Glucosylceramidase
keywords: Gerotarget; aging; brain; polo-like kinase 2; protein phosphatase 2A; α-synuclein