1. Academic Validation
  2. Mesencephalic astrocyte-derived neurotrophic factor inhibits neuroinflammation through autophagy-mediated α-synuclein degradation

Mesencephalic astrocyte-derived neurotrophic factor inhibits neuroinflammation through autophagy-mediated α-synuclein degradation

  • Arch Gerontol Geriatr. 2025 Apr:131:105738. doi: 10.1016/j.archger.2024.105738.
Kai-Ge Zhou 1 Yi-Bin Huang 2 Zi-Wen Zhu 1 Ming Jiang 3 Ling-Jing Jin 4 Qiang Guan 1 Lu-Lu Tian 5 Jing-Xing Zhang 6
Affiliations

Affiliations

  • 1 Department of Neurology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China.
  • 2 School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
  • 3 Department of Neurology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China; Biomedical Research Center, Tongji University Suzhou Institute, Jiangsu, 215101, China.
  • 4 Department of Neurology and Neurological Rehabilitation, Shanghai Yangzhi Rehabilitation Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
  • 5 Department of Pharmacy, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China. Electronic address: lulongtime@126.com.
  • 6 Department of Neurology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China. Electronic address: zhangjxgo@163.com.
Abstract

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder marked by the progressive loss of dopamine neurons in the substantia nigra. α-synuclein (SNCA) aggregation-induced microglia activation and neuroinflammation play vital role in the pathology of PD. Our previous studies showed that mesencephalic astrocyte-derived neurotrophic factor (MANF) could inhibit SNCA accumulation and Lipopolysaccharides (LPS)-induced neuroinflammation, but the specific molecular mechanism remains unclear. In this study, we showed that knock-down the expression of MANF leads to the up-regulation of inflammatory factor tumor necrosis factor-α (TNF-α). Exogenous MANF protein inhibits LPS-induced neuroinflammation in BV2 cells. Additionally, our results indicated that knock-down of the expression of MANF triggered autophagic pathway dysfunction, while exogenous addition of MANF protein or using adeno-associated virus 8 (AAV8) mediated MANF over-expression could activate the autophagic system and subsequently suppress SNCA accumulation. Furthermore, using Autophagy Inhibitor to block autophagic flux, we found that MANF prevented neuroinflammation by autophagy-mediated SNCA degradation. Collectively, this study indicated that MANF has potential therapeutic value for PD. Autophagy and its role in MANF-mediated anti-inflammatory properties may provide new sights that target SNCA pathology in PD.

Keywords

Autophagy; Neuroinflammation; Parkinson's disease; α-synuclein.

Figures
Products