2. Academic Validation
  3. MONNA alleviates MPTP-induced Parkinson's disease in zebrafish by activating TFEB dependently on ER Calcium

MONNA alleviates MPTP-induced Parkinson's disease in zebrafish by activating TFEB dependently on ER Calcium

  • Cell Calcium. 2026 Mar:134:103125. doi: 10.1016/j.ceca.2026.103125.
Meiqin Tang 1,  Ting Luo 2,  Chunlan Kang 3,  Feng Wang 4,  Dongqing Yang 4,  Ruili Cui 5,  Chanjing Li 3,  Yihan Zhang 6,  Yiyao Liu 7,  Min Li 8,  Mei Hu 9,  Ping Li 10
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2 School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, China; Zhongshan Institute for Drug Discovery, Zhongshan 528400, China.
  • 3 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Zhongshan Institute for Drug Discovery, Zhongshan 528400, China.
  • 4 Zhongshan Institute for Drug Discovery, Zhongshan 528400, China; School of Pharmacy, Zunyi Medical University, Zunyi 563000, China.
  • 5 Zhongshan Institute for Drug Discovery, Zhongshan 528400, China; College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 6 Zhongshan Institute for Drug Discovery, Zhongshan 528400, China; University of Chinese Academy of Sciences, Beijing 100049, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 7 Zhongshan Institute for Drug Discovery, Zhongshan 528400, China.
  • 8 Department of Children Health Care, The First People's Hospital of Datong, Datong 037000, China.
  • 9 Pharmacology Laboratory, Zhongshan Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Zhongshan 528401, China. Electronic address: [email protected].
  • 10 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, China; Zhongshan Institute for Drug Discovery, Zhongshan 528400, China; School of Pharmacy, Zunyi Medical University, Zunyi 563000, China; College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; University of Chinese Academy of Sciences, Beijing 100049, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: [email protected].
PMID: 41637953 DOI: 10.1016/j.ceca.2026.103125
Abstract

A-synuclein aggregation is a biomarker of Parkinson's disease (PD) whose feature is the progressive loss of dopaminergic neuron in the middle brain. The removal of a-synuclein aggregation through autophagy-lysosome pathway is a promising strategy for PD treatment. Transcription factor EB (TFEB) is a master regulator of autophagic and lysosomal biogenesis and function. Here, we report a library screen of intracellular CA2+ inducers to identify small-molecule agonists of TFEB and discover MONNA can promote autophagic and lysosomal activity. Notably, MONNA facilitates the reduction of pathological a-synuclein in the Parkinson's disease model both in vitro and in vivo, and ameliorates PD-like behaviors in zebrafish. Mode of action studies reveal MONNA induces TFEB nuclear translocation through a CA2+-dependent mechanism involving Calcineurin (CaN). Endoplasmic reticulum (ER) but not lysosome CA2+ is critical to MONNA-induced TFEB activation and Autophagy induction. Furthermore, Sarcoendoplasmic reticulum calcium ATPase (SERCA) pump of ER modulates TFEB nuclear translocation induced by MONNA. Our findings demonstrate that MONNA is the first ER CA2+-dependent small synthetic TFEB agonist promoting the degradation of a-synuclein aggregates and alleviating Parkinson's disease. This ER CA2+-Calcineurin-TFEB signaling pathway would broaden the way to develop drugs for PD.

Keywords

ER Ca(2+); MONNA; Transcription factor EB (TFEB); a-synuclein; autophagy.

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