Increased α-synuclein oligomerization is associated with decreased activity of glucocerebrosidase in the aging human striatum and hippocampus

Abstract

Aging is associated with an increased risk for Parkinson’s disease and dementia with Lewy bodies, in which α-synuclein (α-syn) oligomerization plays key pathogenic roles. Here, we show that oligomeric α-syn levels increase with age in the human brain and are accompanied by a decrease in the activity of glucocerebrosidase (GCase), a lysosomal enzyme whose dysfunction is linked to the accumulation of oligomeric α-syn. The inverse relationship between oligomeric α-syn levels and GCase activity was more evident in brain regions susceptible to neurodegeneration (i.e., the striatum and hippocampus) than those that are less vulnerable (i.e., the cerebellum and occipital cortex). GCase could potentially regulate α-syn oligomerization, as demonstrated by the decrease in oligomeric α-syn levels caused by a GCase agonist. In vitro experiments showed that GCase activity was more potently inhibited by oligomeric than monomeric α-syn in the lysosome-enriched fractions isolated from brain tissues and cultured neuronal cells. Alterations in oligomeric α-syns and their association with GCase in aging brains may explain the vulnerability of certain brain regions to neurodegeneration in Parkinson’s disease and dementia with Lewy bodies.