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

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.