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PLoS One. 2013 Aug 6;8(8):e70472. doi: 10.1371/journal.pone.0070472. Print 2013.

Autophagic impairment contributes to systemic inflammation-induced dopaminergic neuron loss in the midbrain.

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1
Department of Neurology, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.

Abstract

BACKGROUND:

Neuroinflammation 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.

RESULTS:

Intraperitoneal 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.

CONCLUSION:

Neuroinflammation may cause autophagic impairment, which could in turn result in DA neuron degeneration in midbrain.

PMID:
23936437
PMCID:
PMC3735600
DOI:
10.1371/journal.pone.0070472
[Indexed for MEDLINE]
Free PMC Article
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