Metabolic inflammation exacerbates dopaminergic neuronal degeneration in response to acute MPTP challenge in type 2 diabetes mice.

Abstract

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.

• Authors: Ling Wang, Ying-Qi Zhai, Li-Li Xu, Chen Qiao, Xiu-Lan Sun, Jian-Hua Ding, Ming Lu, Gang Hu
• Journal: Experimental neurology (Exp Neurol) Vol. 251 Pg. 22-9 (Jan 2014) ISSN: 1090-2430 [Electronic] United States
• PMID: 24220636 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Blood Glucose
• Endoplasmic Reticulum Chaperone BiP
• Glial Fibrillary Acidic Protein
• Hspa5 protein, mouse
• Macrophage-1 Antigen

Topics

• Animals
• Blood Glucose (drug effects)
• Diabetes Mellitus, Type 2 (complications, genetics)
• Disease Models, Animal
• Dopaminergic Neurons (drug effects, pathology)
• Endoplasmic Reticulum Chaperone BiP
• Gene Expression Regulation (drug effects, genetics)
• Glial Fibrillary Acidic Protein (metabolism)
• Insulin Resistance
• Liver (metabolism, pathology)
• MPTP Poisoning (chemically induced, complications)
• Macrophage-1 Antigen (metabolism)
• Male
• Mesencephalon (drug effects, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Nerve Degeneration (etiology)
• Pancreas (metabolism, pathology)
• Pancreatitis (chemically induced, etiology)