Bingjie Xie1, Fankai Lin2, Kaleem Ullah3, Lei Peng4, Wei Ding5, Rongji Dai6, Hong Qing7, Yulin Deng8. 1. School of Life Science, Beijing Institute of Technology, No. 5 Zhongguancun Nandajie, Haidian District, Beijing 100081, People's Republic of China. Electronic address: xiebingjie19860128@126.com. 2. School of Life Science, Beijing Institute of Technology, No. 5 Zhongguancun Nandajie, Haidian District, Beijing 100081, People's Republic of China. Electronic address: franklinbit@163.com. 3. School of Life Science, Beijing Institute of Technology, No. 5 Zhongguancun Nandajie, Haidian District, Beijing 100081, People's Republic of China. Electronic address: drkaleemullah@gmail.com. 4. School of Life Science, Beijing Institute of Technology, No. 5 Zhongguancun Nandajie, Haidian District, Beijing 100081, People's Republic of China. Electronic address: play1220@126.com. 5. School of Life Science, Beijing Institute of Technology, No. 5 Zhongguancun Nandajie, Haidian District, Beijing 100081, People's Republic of China. Electronic address: whitenoel@sina.com. 6. School of Life Science, Beijing Institute of Technology, No. 5 Zhongguancun Nandajie, Haidian District, Beijing 100081, People's Republic of China. Electronic address: dairongji@bit.edu.cn. 7. School of Life Science, Beijing Institute of Technology, No. 5 Zhongguancun Nandajie, Haidian District, Beijing 100081, People's Republic of China. Electronic address: hongq16@gmail.com. 8. School of Life Science, Beijing Institute of Technology, No. 5 Zhongguancun Nandajie, Haidian District, Beijing 100081, People's Republic of China. Electronic address: deng@bit.edu.cn.
Abstract
BACKGROUND: Diabetes is associated with an increased risk of Parkinson's disease (PD). Number of studies have suggested that methylglyoxal (MGO) induced by diabetes is related to PD. However, very little is known about its molecular mechanism. On other hand, 1-acetyl-6, 7- dihydroxyl-1, 2, 3, 4- Tetrahydroisoquinoline(ADTIQ) is a dopamine (DA)-derived tetrahydroisoquinoline (TIQ), a novel endogenous neurotoxins, which was first discovered in frozen Parkinson's disease human brain tissue. While ADTIQ precursor methylglyoxal was also found in diabetic patients related to the glucose metabolism and diabetic patients. METHODS: LC-MS/MS, 1H NMR and infrared spectroscopy identified the structure of ADTIQ. The Annexin V-FITC/PI, MTT and western blot analysis were used to measure the neurotoxicity of ADTIQ. The levels of ADTIQ and methylglyoxal were detected by LC-MS/MS. RESULTS: Here we report the chemical synthesis of ADTIQ, demonstrate its biosynthesis in SH-SY5Y neuroblastoma cell line and investigate its role in the pathogenesis of PD. In addition, a significant increase in the level of ADTIQ was detected in the brains of transgenic mice expressing mutant forms (A53T or A30P) of α-synuclein. ADTIQ also reduced the cell viability and induced mitochondrial apoptosis in dopaminergic cells, suggesting that ADTIQ acts as an endogenous neurotoxin and potentially involved in the pathogenesis of PD. Methylglyoxal, a major byproduct of glucose metabolism and abnormalities in glucose metabolism could influence the levels of ADTIQ. Consistent with the hypothesis, increased levels of ADTIQ and methylglyoxal were detected in the striatum of diabetic rats and SH-SY5Y cells cultured in the presence of high glucose concentrations. CONCLUSIONS: Increased levels of ADTIQ could be related with Hyperglycemia and death of dopaminergic neurons. GENERAL SIGNIFICANCE: The increased levels of ADTIQ could be a reason of dopamine neuron dysfunction in diabetes. Therefore, ADTIQ may play a key role in increasing the risk for PD in patients with diabetes.
BACKGROUND:Diabetes is associated with an increased risk of Parkinson's disease (PD). Number of studies have suggested that methylglyoxal (MGO) induced by diabetes is related to PD. However, very little is known about its molecular mechanism. On other hand, 1-acetyl-6, 7- dihydroxyl-1, 2, 3, 4- Tetrahydroisoquinoline(ADTIQ) is a dopamine (DA)-derived tetrahydroisoquinoline (TIQ), a novel endogenous neurotoxins, which was first discovered in frozen Parkinson's diseasehuman brain tissue. While ADTIQ precursor methylglyoxal was also found in diabeticpatients related to the glucose metabolism and diabeticpatients. METHODS: LC-MS/MS, 1H NMR and infrared spectroscopy identified the structure of ADTIQ. The Annexin V-FITC/PI, MTT and western blot analysis were used to measure the neurotoxicity of ADTIQ. The levels of ADTIQ and methylglyoxal were detected by LC-MS/MS. RESULTS: Here we report the chemical synthesis of ADTIQ, demonstrate its biosynthesis in SH-SY5Yneuroblastoma cell line and investigate its role in the pathogenesis of PD. In addition, a significant increase in the level of ADTIQ was detected in the brains of transgenic mice expressing mutant forms (A53T or A30P) of α-synuclein. ADTIQ also reduced the cell viability and induced mitochondrial apoptosis in dopaminergic cells, suggesting that ADTIQ acts as an endogenous neurotoxin and potentially involved in the pathogenesis of PD. Methylglyoxal, a major byproduct of glucose metabolism and abnormalities in glucose metabolism could influence the levels of ADTIQ. Consistent with the hypothesis, increased levels of ADTIQ and methylglyoxal were detected in the striatum of diabeticrats and SH-SY5Y cells cultured in the presence of high glucose concentrations. CONCLUSIONS: Increased levels of ADTIQ could be related with Hyperglycemia and death of dopaminergic neurons. GENERAL SIGNIFICANCE: The increased levels of ADTIQ could be a reason of dopamineneuron dysfunction in diabetes. Therefore, ADTIQ may play a key role in increasing the risk for PD in patients with diabetes.
Authors: Annadurai Anandhan; Maria S Jacome; Shulei Lei; Pablo Hernandez-Franco; Aglaia Pappa; Mihalis I Panayiotidis; Robert Powers; Rodrigo Franco Journal: Brain Res Bull Date: 2017-03-21 Impact factor: 4.077