2. Academic Validation
  3. Phillyrin promotes autophagosome formation in A53T-αSyn-induced Parkinson's disease model via modulation of REEP1

Phillyrin promotes autophagosome formation in A53T-αSyn-induced Parkinson's disease model via modulation of REEP1

  • Phytomedicine. 2024 Nov:134:155952. doi: 10.1016/j.phymed.2024.155952.
Li-Feng-Rong Qi 1,  Yuci Liu 2,  Shuai Liu 2,  Lin Xiang 3,  Zhiyuan Liu 2,  Qingling Liu 4,  Jin-Quan Zhao 4,  Xiaojun Xu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: 1520210063@cpu.edu.cn.
  • 2 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 3 Department of Translational Medicine Research Institute, Jiangsu Yifengrong Biotechnology Co., Ltd., Nanjing, Jiangsu, China.
  • 4 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
  • 5 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Pharmacy, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China; Center for Innovative Traditional Chinese Medicine Target and New Drug Research, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, China. Electronic address: xiaojunxu@zju.edu.cn.
PMID: 39178680 DOI: 10.1016/j.phymed.2024.155952
Abstract

Background: The preservation of autophagosome formation presents a promising strategy for tackling neurological disorders, such as Parkinson's disease (PD). Mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) serve not only as a focal point linked to various neurological disorders but also play a crucial role in supporting the biogenesis of autophagosomes.

Purpose: This investigation aimed to elucidate the neuroprotective properties of phillyrin against PD and its underlying mechanisms in promoting autophagosome formation.

Methods: ER and mitochondria co-localization was assessed via fluorescent staining. Annexin V-fluorescein isothiocyanate (FITC) fluorescence was employed to quantify accessible cardiolipin (CL) on mitochondrial surfaces. The levels of CL within the MAM fraction of SH-SY5Y cells were evaluated using a CL probe assay kit. Monodansylcadaverine staining was utilized to detect autophagosome formation in SH-SY5Y cells. In an A53T-alpha-synuclein (αSyn)-induced PD mouse model, the anti-PD properties of phillyrin were assessed using open field, pole climbing, and rotarod tests, as well as immunohistochemistry staining of TH+ neurons in the brain sections.

Results: In A53T-αSyn-treated SH-SY5Y cells, phillyrin facilitated autophagosome formation by suppressing CL externalization and restoring MAM integrity. Phillyrin enhanced the localization of receptor expression-enhancing protein 1 (REEP1) within MAM and mitochondria, bolstering MAM formation. Increased REEP1 levels in mitochondria, attributed to phillyrin, enhanced the interaction between REEP1 and NDPK-D, thereby reducing CL externalization. Furthermore, phillyrin exhibited a dose-dependent enhancement of motor function in mice, accompanied by an increase in the abundance of dopaminergic neurons within the substantia nigra.

Conclusions: These findings illuminate phillyrin's ability to enhance MAM formation through upregulation of REEP1 expression within MAM, while concurrently attenuating CL externalization via the REEP1-NDPK-D interaction. These mechanisms bolster autophagosome biogenesis, offering resilience against A53T-αSyn-induced PD. Thus, our study advances the understanding of phillyrin's complex mechanisms and underscores its potential as a therapeutic approach for PD, opening new avenues in natural product pharmacology.

Keywords

Autophagosome; Cardiolipin; Mitochondria-associated ER membranes; NDPK-D; Parkinson's disease; REEP1; phillyrin.

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