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.

衰老与路易小体的帕金森氏病和痴呆症风险增加相关，其中α-突触核蛋白（α-syn）寡聚发挥关键的致病作用。在这里，我们显示寡聚α-syn水平随人脑年龄的增长而增加，并伴有葡萄糖脑苷脂酶（GCase）活性的降低，该酶是一种溶酶体酶，其功能障碍与寡聚α-syn的积累有关。与易感性较差的大脑区域（即小脑和枕叶皮质）相比，在易发生神经变性的大脑区域（即纹状体和海马体）中，寡聚α-syn水平与GCase活性之间的反比关系更为明显。GCase可能潜在地调节α-syn的寡聚，如GCase激动剂引起的寡聚α-syn水平降低所证明的。体外实验表明，在从脑组织和培养的神经元细胞中分离得到的富含溶酶体的组分中，寡聚体比单体α-syn更有效地抑制了GCase的活性。衰老的大脑中寡聚α-syns的变化及其与GCase的关联可能解释了某些大脑区域对帕金森氏病和路易小体痴呆症的神经变性的脆弱性。