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


CONCLUSIONS
Neuroinflammation may cause autophagic impairment, which could in turn result in DA neuron degeneration in midbrain.
Department of Neurology, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Hui-Fen
HF
Zheng
Ya-Ping
YP
Yang
Li-Fang
LF
Hu
Mei-Xia
MX
Wang
Fen
F
Wang
Li-Dan
LD
Cao
Da
D
Li
Cheng-Jie
CJ
Mao
Kang-Ping
KP
Xiong
Jian-Da
JD
Wang
Chun-Feng
CF
Liu
D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002452:Cell Count; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology*; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008636:Mesencephalon / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016716:PC12 Cells; D010300:Parkinson Disease / Q000473:pathology; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051844:alpha-Synuclein / Q000378:metabolism
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D051844:alpha-Synuclein