Increased oligomerization and phosphorylation of α-synuclein are associated with decreased activity of glucocerebrosidase and protein phosphatase 2A in aging monkey brains

Aging is associated with an increased risk for Parkinson's disease and dementia with Lewy bodies, in which alpha-synuclein (alpha-syn) oligomerization plays key pathogenic roles. Here, we show that oligomeric alpha-syn levels increase with age in the brain of cynomolgus monkeys and are accompanied by a decrease in the expression and activity of glucocerebrosidase (GCase), a lysosomal enzyme whose dysfunction is linked to accumulation of oligomeric alpha-syn. Besides, levels of alpha-syn phosphorylated at serine 129 (pS129 alpha-syn), a modification that promotes alpha-syn oligomerization also increase with age in the brain and is associated with a reduction in the activity of protein phosphatase 2A (PP2A), an enzyme that facilitates alpha-syn dephosphorylation. The inverse relationship between levels of oligomeric alpha-syn and pS129 alpha-syn and activity of GCase and PP2A was more evident in brain regions susceptible to neurodegeneration (i.e., the striatum and hippocampus) than those that are less vulnerable (i.e., cerebellum and occipital cortex). In vitro experiments showed that GCase activity was more potently inhibited by oligomeric than by monomeric alpha-syn in the lysosome-enriched fractions isolated from brain tissues and cultured neuronal cells. Inhibition of GCase activity induced an elevation of oligomeric alpha-syn levels, which was shown to increase pS129 alpha-syn levels and reduce PP2A activity in cultured neuronal cells. The alterations in oligomeric and pS129 alpha-syns and their association with GCase and PP2A in aging brains may explain the vulnerability of certain brain regions to neurodegeneration in Parkinson's disease and dementia with Lewy bodies. (C) 2015 Elsevier Inc. All rights reserved.