Autophagic Impairment Contributes to Systemic Inflammation-Induced Dopaminergic Neuron Loss in the Midbrain

作者：Zheng Hui Fen; Yang Ya Ping; Hu Li Fang; Wang Mei Xia; Wang Fen; Cao Li Dan; Li Da; Mao Cheng Jie; Xiong Kang Ping; Wang Jian Da; Liu Chun Feng^*

来源：PLos One, 2013, 8(8): e70472.

DOI：10.1371/journal.pone.0070472

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 alpha-synuclein (alpha-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 alpha-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-alpha induced cell death in PC12 cells. Moreover, a sublethal dose of TNF-alpha (50 ng/ml) increased the expression of LC3-II, p62, and alpha-SYN, implying that TNF-alpha triggered autophagic impairment in cells.
Conclusion: Neuroinflammation may cause autophagic impairment, which could in turn result in DA neuron degeneration in midbrain.

• 出版日期2013-8-6
• 单位苏州大学