Secretome Analyses Identify FKBP4 as a GBA1-Associated Protein in CSF and iPS Cells from Parkinson’s Disease Patients with GBA1 Mutations

Rika Kojima, Wojciech Paslawski, Guochang Lyu, Ernest Arenas, Xiaoqun Zhang, Per Svenningsson
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Abstract

Mutations in the GBA1 gene increase the risk of developing Parkinson’s disease (PD). However, most carriers of GBA1 mutations do not develop PD throughout their lives. The mechanisms of how GBA1 mutations contribute to PD pathogenesis remain unclear. Cerebrospinal fluid (CSF) is used for detecting pathological conditions of diseases, providing insights into the molecular mechanisms underlying neurodegenerative disorders. In this study, we utilized the proximity extension assay to examine the levels of metabolism-linked protein in the CSF from 17 PD patients carrying GBA1 mutations (GBA1-PD) and 17 idiopathic PD (iPD). The analysis of CSF secretome in GBA1-PD identified 11 significantly altered proteins, namely FKBP4, THOP1, GLRX, TXNDC5, GAL, SEMA3F, CRKL, APLP1, LRP11, CD164, and NPTXR. To investigate GBA1-associated CSF changes attributed to specific neuronal subtypes responsible for PD, we analyzed the cell culture supernatant from GBA1-PD-induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic (mDA) neurons. The secretome analysis of GBA1-PD iPSC-derived mDA neurons revealed that five differently regulated proteins overlapped with those identified in the CSF analysis: FKBP4, THOP1, GLRX, GAL, and CRKL. Reduced intracellular level of the top hit, FKPB4, was confirmed via Western Blot. In conclusion, our findings identify significantly altered CSF GBA1-PD-associated proteins with FKPB4 being firmly attributed to mDA neurons.
分泌组分析确定 FKBP4 是 GBA1 基因突变的帕金森病患者 CSF 和 iPS 细胞中的 GBA1 相关蛋白
GBA1 基因突变会增加帕金森病(PD)的患病风险。然而,大多数 GBA1 基因突变携带者终生都不会患帕金森病。GBA1 基因突变如何导致帕金森病发病的机制仍不清楚。脑脊液(CSF)可用于检测疾病的病理状态,为神经退行性疾病的分子机制提供洞察力。在这项研究中,我们利用邻近延伸试验检测了17例携带GBA1突变的帕金森病患者(GBA1-PD)和17例特发性帕金森病患者(iPD)脑脊液中代谢相关蛋白的水平。对GBA1-PD患者脑脊液分泌组的分析发现了11种明显改变的蛋白质,即FKBP4、THOP1、GLRX、TXNDC5、GAL、SEMA3F、CRKL、APLP1、LRP11、CD164和NPTXR。为了研究与GBA1相关的CSF变化归因于导致帕金森病的特定神经元亚型,我们分析了GBA1-PD诱导的多能干细胞(iPSC)衍生的中脑多巴胺能(mDA)神经元的细胞培养上清。对GBA1-PD iPSC衍生的mDA神经元进行的分泌组分析表明,五种不同的调控蛋白与CSF分析中发现的蛋白重叠:FKBP4、THOP1、GLRX、GAL和CRKL。通过 Western 印迹,证实了最热门的 FKPB4 细胞内水平降低。总之,我们的研究结果确定了 CSF GBA1-PD 相关蛋白的显著变化,其中 FKPB4 被确定归因于 mDA 神经元。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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