New drug discoveries fighting for Parkinson’s Disease
Parkinson’s Disease (PD) is a progressive neurodegenerative disorder which impairs the motor functions. The motor symptoms include shaking, difficulty in walking, balance, and coordination. These issues usually begin gradually, yet become worse over time, thus PD is considered an aging-associated neurodegenerative disorder. New research is urgently required to further the understanding of PD and aid those who suffer from it with new drugs. An HKBU team is currently researching possible new drugs to aid those who suffer from PD in a project titled “New Drug Discovery for Aging-associated Neurodegenerative Disorders - Parkinson’s Disease.”
To investigate this project, one of the research team’s objectives is to examine the efficacy and action mechanisms of autophagy enhancers in degrading alpha-synuclein aggregates to prevent neuronal loss and motor function deficit in PD animal models. Discoveries were made surrounding curcumin analog C1 and celastrol, two autophagy enhancers. Curcumin analog C1 was found to both stimulate nuclear translocation of the major autophagy regulator, transcription factor EB (TFEB), and significantly rescued 6-OHDA/AA induced neuronal cell death in cellular and animal models of PD (as illustrated in Figure 1). Meanwhile, their on-going study reveals the role of celastrol as an autophagy enhancer by targeting TFEB-mediated autophagy and lysosome biogenesis, which can rescue motor dysfunction and neuronal loss in an MPTP-induced PD animal model. It is hoped that their studies will continue providing new drug discoveries fighting against the devastating effects of PD.
The project is a collaboration spearheaded by Professor Min Li, Associate Dean of the School of Chinese Medicine. Joining Professor Li are colleagues Drs King-ho Cheung, Chuanbin Yang and Juxian Song from the School of Chinese Medicine. Drs Edmond Ma and Ken Leung from the Department of Chemistry, and Dr Allen Cheung from the Department of Biology have also lent support for this project.
Figure 1 Autophagy enhancers activate TFEB-mediated autophagy to protect against 6-OHDA/AA toxicity in PD models. The generation of ROS induced by 6-OHDA/AA leads to mitochondria dysfunction, which initiates the apoptotic signaling in cells. Meanwhile, the ROS signal also can be sensed by the calcium channel MCOLN1 on the membrane of lysosome. The release of Ca2+ from lysosome leads to calcineurin activation and de-phosphorylation of TFEB. Autophagy enhancers like Torin 1 and C1 also can lead to TFEB activation. The activated TFEB translocate to the nucleus to initiate autophagy–lysosome–related genes transcription, which promotes the autophagic clearance of damaged mitochondria and accumulated ROS to rescue cells from death.