Abstract
BackgroundNeuroinflammation plays an important role in the pathogenesis of Parkinson’s disease (PD), inducing and accelerating dopaminergic (DA) neuron loss. Autophagy, a critical mechanism for clearing misfolded or aggregated proteins such as α-synuclein (α-SYN), may affect DA neuron survival in the midbrain. However, whether autophagy contributes to neuroinflammation-induced toxicity in DA neurons remains unknown.ResultsIntraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) into young (3-month-old) and aged (16-month-old) male C57BL/6J mice was observed to cause persistent neuroinflammation that was associated with a delayed and progressive loss of DA neurons and accumulation of α-SYN in the midbrain. The autophagic substrate-p62 (SQSTM1) persistently increased, whereas LC3-II and HDAC6 exhibited early increases followed by a decline. In vitro studies further demonstrated that TNF-α induced cell death in PC12 cells. Moreover, a sublethal dose of TNF-α (50 ng/ml) increased the expression of LC3-II, p62, and α-SYN, implying that TNF-α triggered autophagic impairment in cells.ConclusionNeuroinflammation may cause autophagic impairment, which could in turn result in DA neuron degeneration in midbrain.
Highlights
Multiple lines of evidence have implicated neuroinflammation in the onset and progression of Parkinson’s disease (PD) and other neurodegenerative disorders [1]
Animals were randomly divided into four groups (n = 8–10 each group): (I) 16-month-old mice treated with saline (16-C); (II) 16-month-old mice treated with LPS (16-L); (III) 3-month-old mice treated with saline (3-C); and (IV) 3-month-old mice treated with LPS (3-L)
The number of residual DA neurons and the activation of microglia were detected by immunohistochemistry
Summary
Multiple lines of evidence have implicated neuroinflammation in the onset and progression of Parkinson’s disease (PD) and other neurodegenerative disorders [1]. Anti-inflammatory drugs have been reported to reduce dopaminergic (DA) neuron loss in various PD models [5,6]. Researchers have demonstrated that a single intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) into C57BL/6J adult mice caused a delay of neuronal loss in SN. This unique property mimics the chronic progression of PD. This is helpful in studying inflammation-related neurodegeneration and its related cellular and molecular mechanisms [14]. Neuroinflammation plays an important role in the pathogenesis of Parkinson’s disease (PD), inducing and accelerating dopaminergic (DA) neuron loss. Whether autophagy contributes to neuroinflammation-induced toxicity in DA neurons remains unknown
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