The orphan G protein-coupled receptor 37 (GPR37), widely associated with Parkinson’s disease (PD), undergoes proteolytic processing under physiological conditions. The N-terminus domain is proteolyzed by a disintegrin and metalloproteinase 10 (ADAM-10), which generates various membrane receptor forms and ectodomain shedding (ecto-GPR37) in the extracellular environment. We investigated the processing and density of GPR37 in several neurodegenerative conditions, including Lewy body disease (LBD), multiple system atrophy (MSA), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Alzheimer’s disease (AD). The presence of ecto-GPR37 peptides in the cerebrospinal fluid (CSF) of PD, MSA, CBD and PSP patients was assessed through an in-house nanoluciferase-based immunoassay. This study identified increased receptor processing in early-stage LBD within the PFC and striatum, key brain areas in neurodegeneration. In MSA only the 52 kDa form of GPR37 appeared in the striatum. This form was also significantly elevated in the striatum of AD necropsies. On the contrary, GPR37 processing remained unchanged in the brains of CBD and PSP patients. Furthermore, while CSF ecto-GPR37 increased in PD patients, its levels remained unchanged in MSA, CBD, and PSP subjects. Importantly, patients with PD with rapid progression of the disease did not have elevated ecto-GPR37 in the CSF, while those with slow progression showed a significant increase, suggesting a possible prognostic use of ecto-GPR37 in PD. This research underscores the distinctive processing and density patterns of GPR37 in neurodegenerative diseases, providing crucial insights into its potential role as an indicator of PD progression rates.

孤儿 G 蛋白偶联受体 37 (GPR37) 与帕金森病 (PD) 广泛相关，在生理条件下会经历蛋白水解过程。 N 末端结构域被解整合素和金属蛋白酶 10 (ADAM-10) 蛋白水解，在细胞外环境中产生各种膜受体形式和胞外域脱落 (ecto-GPR37)。我们研究了 GPR37 在几种神经退行性疾病中的加工和密度，包括路易体病 (LBD)、多系统萎缩 (MSA)、皮质基底节变性 (CBD)、进行性核上性麻痹 (PSP) 和阿尔茨海默病 (AD)。通过内部基于纳米荧光素酶的免疫测定来评估 PD、MSA、CBD 和 PSP 患者脑脊液 (CSF) 中 ecto-GPR37 肽的存在。这项研究发现，早期 LBD 中 PFC 和纹状体（神经退行性疾病的关键大脑区域）内的受体处理增加。在 MSA 中，纹状体中仅出现 52 kDa 形式的 GPR37。这种形式在 AD 尸检的纹状体中也显着升高。相反，GPR37 处理在 CBD 和 PSP 患者的大脑中保持不变。此外，虽然 PD 患者中 CSF ecto-GPR37 增加，但 MSA、CBD 和 PSP 受试者中其水平保持不变。重要的是，疾病快速进展的 PD 患者脑脊液中 ecto-GPR37 没有升高，而进展缓慢的 PD 患者则显着升高，这表明 ecto-GPR37 在 PD 中可能用于预后预测。这项研究强调了 GPR37 在神经退行性疾病中独特的处理和密度模式，为其作为 PD 进展率指标的潜在作用提供了重要的见解。