Abstract：
Polypeptide N-acetylgalactosamine transferase 9 (GALNT9) catalyzes the initial step of mucin-type O-glycosylation via linking N-acetylgalactosamine (GalNAc) to serine/threonine in a protein. To unravel the association of GALNT9 with Parkinson\'s disease (PD), a progressive neurodegenerative disorder, GALNT9 levels were evaluated in the patients with PD and mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and statistically analyzed based on the GEO datasets of GSE114918 and GSE216281. Glycoproteins with exposing GalNAc were purified using lectin affinity chromatography and identified by LC-MS/MS. The influence of GALNT9 on cells was evaluated via introducing a GALNT9-specific siRNA into SH-SY5Y cells. Consequently, GALNT9 deficiency was found to occur under PD conditions. GALNT9 silencing contributed to a causative factor in PD pathogenesis via reducing the levels of intracellular dopamine, tyrosine hydroxylase and soluble α-synuclein, and promoting α-synuclein aggregates. MS identification revealed 14 glycoproteins. 5 glycoproteins, including ACO2, ATP5B, CKB, CKMT1A, ALDOC, were associated with energy metabolism. GALNT9 silencing resulted in mitochondrial dysfunctions via increasing ROS accumulation, mitochondrial membrane depolarization, mPTPs opening, Ca2+ releasing and activation of the CytC-related apoptotic pathway. The dysfunctional mitochondria then triggered mitophagy, possibly intermediated by adenine nucleotide translocase 1. Our study suggests that GALNT9 is potentially developed into an auxiliary diagnostic index and therapeutic target of PD.
摘要：
多肽N-乙酰半乳糖胺转移酶9（GALNT9）通过将N-乙酰半乳糖胺（GalNAc）连接到蛋白质中的丝氨酸/苏氨酸来催化粘蛋白型O糖基化的初始步骤。解开GALNT9与帕金森病（PD）的关联，进行性神经退行性疾病，在PD患者和用1-甲基-4-苯基-1,2,3,6-四氢吡啶治疗的小鼠中评估GALNT9水平，并基于GSE114918和GSE216281的GEO数据集进行统计分析。使用凝集素亲和色谱法纯化暴露于GalNAc的糖蛋白，并通过LC-MS/MS进行鉴定。通过将GALNT9特异性siRNA引入SH-SY5Y细胞来评估GALNT9对细胞的影响。因此,发现在PD条件下发生GALNT9缺乏。GALNT9沉默有助于通过降低细胞内多巴胺的水平在PD发病机理的致病因素，酪氨酸羟化酶和可溶性α-突触核蛋白，促进α-突触核蛋白聚集。MS鉴定揭示了14种糖蛋白。5糖蛋白，包括ACO2，ATP5B，CKB,CKMT1A,ALDOC,与能量代谢有关。GALNT9沉默通过增加ROS积累导致线粒体功能障碍，线粒体膜去极化，mPTP打开,Ca2+释放和CytC相关凋亡途径的激活。然后功能失调的线粒体引发了线粒体自噬，可能由腺嘌呤核苷酸转位酶1介导。我们的研究表明GALNT9有可能发展成为PD的辅助诊断指标和治疗靶点。
