Researchers may have found a significant breakthrough that may help us better detect and treat Parkinson’s disease (PD). The protein alpha-synuclein (Syn) is linked to Parkinson’s disease, and this study, conducted by an enthusiastic team of experts, delves into the delicate relationship between mitochondrial malfunction, mitophagy, and the toxicity caused by this protein. Â
For some years, Parkinson’s disease researchers have suspected mitochondrial dysfunction. The study discovered that mitophagy, or the selective removal of malfunctioning mitochondria, is critical for maintaining a continual supply of viable mitochondria. The authors point out that a PARKIN gene defect is directly linked to mitophagy in autosomal recessive Parkinson’s disease (AR-PD).
PARKIN deficiency delays the course of Parkinson’s disease by disrupting the mitophagy process. Using this as a starting point, the researchers investigate how faulty mitophagy leads to Syn toxicity. Syn is a protein that has been linked to Alzheimer’s and Parkinson’s disease when mutated or duplicated.
The findings indicate that Syn interferes with mitochondrial function by binding to TOM20 on the mitochondrial membrane, blocking protein import into mitochondria. Defective mitochondria produce more reactive oxygen species (ROS), extending the vicious cycle of sickness. Â
It has been proposed that USP30, a deubiquitylating enzyme found on the outer mitochondrial membrane, can be selectively regulated to alter mitophagy. In a mouse model of Parkinson’s disease, genetic suppression of the Usp30 gene and pharmacological reduction of USP30 enzymatic activity with MTX115325 dramatically improved mitophagy and provided considerable protection from Syn toxicity. Â
According to the findings, reducing USP30’s enzymatic activity with MTX115325 or disrupting USP30 in Usp30 knockout mice improves mitophagy considerably, providing considerable protection against Syn-induced neurotoxicity. The researchers also discovered that Usp30 knockout mice have potential as a therapy for aging-related liver damage. Â
Despite its good findings, the paper admits its limits and offers issues for future research. The researchers plan to investigate the processes behind the observed alterations and examine if the Usp30 deletion interacts with other PD-related genes. Â
Because of the findings of this study, we now have much better knowledge of the complicated interaction between mitochondrial homeostasis, mitophagy, and syn toxicity in Parkinson’s disease. The findings suggest that targeting USP30 may be a promising avenue for developing innovative treatment techniques to delay or change the progression of Parkinson’s disease, providing hope to the millions of people affected by this cruel neurodegenerative malady.Â
Journal ReferenceÂ
Fang, T.-S. Z., Sun, Y., Pearce, A. C., Eleuteri, S., Kemp, M., Luckhurst, C. A., … Simon, D. K. (2023). Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson’s disease mouse model. Retrieved from https://www.nature.com/articles/s41467-023-42876-1#Sec11Â
