Imagine you’re on a quest to activate a complex pathway in your body called the PINK1/Parkin pathway. Sounds like a daunting task, right? Scientists have been interested in drugging this pathway to treat Parkinson’s disease, but it turns out that activating the key players, Parkin and PINK1, is not as easy as it seems. This review dives into the challenges faced in activating these targets effectively. It discusses how simply activating Parkin biochemically may not translate to activation within cells. Additionally, attempts to activate PINK1 with certain compounds called kinetin analogs have not shown promising results in animal models. However, there may be hope in activating the mitophagy pathway, which removes dysfunctional mitochondria, using inhibitors of a protein called USP30. Interestingly, another potential way to activate Parkin involves a cellular stress response called the AMPK-ULK1 pathway. The article concludes by mentioning ongoing clinical trials that will test the effectiveness of these different approaches. If you’re curious about the intricate world of Parkinson’s research and how scientists are tackling the challenge of activating the PINK1/Parkin pathway, dive into this fascinating article!
There has been long-term interest in drugging the PINK1-Parkin pathway with therapeutics as a treatment for Parkinson’s disease (PD). Despite significant structural data on Parkin as well as the PINK1 kinase and the multiple conformational changes it undergoes, activation of these targets is non-trivial. This review highlights small molecule screening results that suggests that activation of Parkin biochemically does not necessarily translate to activation of Parkin within cells. There are also issues with activation of PINK1 with kinetin analogs, which do not appear to rescue rodent models of PD. The counter-measure of activating the mitophagy pathway with deubiquitinase (DUB) inhibitors such as USP30 inhibitors is progressing in the clinic for kidney disease and the proof of biology for this target will be tested in these trials. An alternative mechanism of activating Parkin in response to oxidative stress via Parkin phosphorylation by the AMPK-ULK1 pathway may be a simpler way to lower the energy barrier Parkin activation.
Dr. David Lowemann, M.Sc, Ph.D., is a co-founder of the Institute for the Future of Human Potential, where he leads the charge in pioneering Self-Enhancement Science for the Success of Society. With a keen interest in exploring the untapped potential of the human mind, Dr. Lowemann has dedicated his career to pushing the boundaries of human capabilities and understanding.
Armed with a Master of Science degree and a Ph.D. in his field, Dr. Lowemann has consistently been at the forefront of research and innovation, delving into ways to optimize human performance, cognition, and overall well-being. His work at the Institute revolves around a profound commitment to harnessing cutting-edge science and technology to help individuals lead more fulfilling and intelligent lives.
Dr. Lowemann’s influence extends to the educational platform BetterSmarter.me, where he shares his insights, findings, and personal development strategies with a broader audience. His ongoing mission is shaping the way we perceive and leverage the vast capacities of the human mind, offering invaluable contributions to society’s overall success and collective well-being.