A newly discovered neurotoxin ADTIQ associated with hyperglycemia and Parkinson's disease.
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.


CONCLUSIONS
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.
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.
Bingjie
B
Xie
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.
Fankai
F
Lin
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.
Kaleem
K
Ullah
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.
Lei
L
Peng
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.
Wei
W
Ding
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.
Rongji
R
Dai
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.
Hong
H
Qing
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.
Yulin
Y
Deng
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009498:Neurotoxins / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D010300:Parkinson Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011765:Pyruvaldehyde / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
C573869:1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline; D050505:Mutant Proteins; D009498:Neurotoxins; D044005:Tetrahydroisoquinolines; D051844:alpha-Synuclein; D011765:Pyruvaldehyde; D005947:Glucose
1-Acetyl-6,7-dihydroxyl-1,2,3,4-tetrahydroisoquinoline (ADTIQ); Diabetes; Methylglyoxal; Parkinson's disease (PD)