Metabolic inflammation exacerbates dopaminergic neuronal degeneration in response to acute MPTP challenge in type 2 diabetes mice.
Parkinson's disease (PD), one of the most common neurodegenerative diseases, is characterized by the loss of dopaminergic neurons in the substantia nigra. Increasing epidemiological evidence has indicated that type 2 diabetes (T2D) may be implicated in the pathogenesis of PD. However, the exact association and the underlying mechanism remain unclear. In the present study, ob/ob and db/db mice, the well accepted T2D models, were acutely treated with MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) to mimic PD-like neural injury. We found that insulin signaling impairment occurred not only in pancreas and livers, but also in the midbrain of ob/ob and db/db mice. Notably, the expressions of monomeric and oligomeric α-synuclein as well as endoplasmic reticulum stress markers (CHOP and GRP78) were significantly upregulated in both pancreas and midbrain of T2D mice, accompanied by the increased activation of NLRP3 inflammasomes to produce excess IL-1β. Furthermore, we found that acute MPTP administration aggravated the loss of dopaminergic neurons and increased the activation of glial cells in the substantia nigra of db/db mice. Collectively, these findings demonstrate that α-synuclein accumulation and neuroinflammation are aggravated in the midbrain of T2D mice and T2D mice are more susceptible to the neurotoxicity induced by MPTP. Our study indicates that metabolic inflammation exacerbates DA neuronal degeneration in the progress of PD, which will provide a novel insight into the etiology of PD.
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, PR China.
Ling
L
Wang
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, PR China.
Ying-Qi
YQ
Zhai
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, PR China.
Li-Li
LL
Xu
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, PR China.
Chen
C
Qiao
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, PR China.
Xiu-Lan
XL
Sun
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, PR China.
Jian-Hua
JH
Ding
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, PR China. Electronic address: lum@njmu.edu.cn.
Ming
M
Lu
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, PR China. Electronic address: ghu@njmu.edu.cn.
Gang
G
Hu
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism / Q000473:pathology; D020267:MPTP Poisoning / Q000139:chemically induced / Q000150:complications*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009410:Nerve Degeneration / Q000209:etiology*; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000209:etiology
D001786:Blood Glucose; D000091342:Endoplasmic Reticulum Chaperone BiP; D005904:Glial Fibrillary Acidic Protein; C000717248:Hspa5 protein, mouse; D016177:Macrophage-1 Antigen
ER stress; Metabolic inflammation; NLRP3 inflammasome; Parkinson's disease; Type 2 diabetes; α-Synuclein