Researchers at the University of Dundee have made significant progress in understanding how a particular molecular switch protects the brain from Parkinson’s disease. By uncovering the mechanisms that activate the protective PINK1 enzyme, scientists have opened new pathways for potential treatments to slow or stop the progression of this debilitating condition.
Their findings were recently published in Science Advances.
Parkinson’s disease is a chronic and progressive neurological disorder that affects millions of people worldwide. It primarily impacts movement control, leading to symptoms such as tremors, stiffness, slowness of movement, and difficulty with balance and coordination. These symptoms are caused by the degeneration of dopamine-producing neurons in a specific area of the brain called the substantia nigra. As these neurons die, dopamine levels drop, resulting in the characteristic symptoms of Parkinson’s disease.
While the exact cause of Parkinson’s remains unknown, several factors are thought to contribute to its development. These include genetic mutations, environmental exposures, and aging. Among the genetic factors, mutations in the PINK1 gene have been identified as one of the causes of early-onset Parkinson’s disease.
PINK1 is known to play a protective role in brain cells by helping to manage cellular stress and maintain mitochondrial function. Mitochondria are the powerhouses of cells, generating the energy needed for cellular activities. When mitochondria are damaged, it can lead to cell death and contribute to the progression of Parkinson’s disease.
The primary motivation behind the new study was to better understand the mechanisms by which the PINK1 gene protects brain cells from damage and degeneration. Previous research had established that PINK1 is crucial for activating a protective pathway that clears damaged mitochondria and proteins from cells. This pathway involves two key proteins, ubiquitin and Parkin, which work together to eliminate damaged components and maintain cellular health.
However, despite knowing the protective role of PINK1, the precise mechanism by which PINK1 is activated remained unclear. Understanding this activation process is critical because it could lead to the development of new therapies that enhance PINK1’s protective effects. Such therapies could potentially slow or halt the progression of Parkinson’s disease, addressing a significant unmet need as there are currently no treatments available that can stop or reverse the condition.
To address this knowledge gap, the researchers aimed to uncover how PINK1 is switched on and how it interacts with other cellular components to exert its protective function. The international research team, which included scientists from the UK, Netherlands, and Germany, utilized a combination of biological experiments and artificial intelligence to model the activation process of PINK1. They focused on how PINK1 interacts with the Translocase of the Outer Membrane (TOM) complex, a key component at the surface of mitochondria.
The researchers discovered that PINK1 is activated through a unique relay mechanism involving its interaction with specific subunits of the TOM complex, particularly TOM20 and TOM70. These subunits play crucial roles in stabilizing and activating PINK1 at the mitochondrial membrane.
The model proposed by the researchers indicates that PINK1 is initially stabilized at the TOM complex through interactions with TOM20 and TOM70. This stabilization is essential for PINK1 to exert its protective function, as it allows the enzyme to target and clear damaged proteins and mitochondria effectively. The study identified unique structural elements within PINK1 that are not found in other enzymes, which are critical for this relay switch mechanism. These elements facilitate the interaction between PINK1 and the TOM complex, enabling the enzyme to become active and perform its protective role.
Another significant finding was the identification of several previously unknown interactions between PINK1 and the TOM complex. These interactions are mediated by distinct regions within PINK1, which the researchers mapped using both experimental data and computational models. This detailed mapping provides a comprehensive understanding of how PINK1 is recruited and activated at the mitochondrial membrane.
“As a clinician who treats Parkinson’s patients, the goal of our research is to discover fundamental mechanisms that may point to new ways to better treat the disease in the future,” said Professor Miratul Muqit, consultant neurologist at the Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU) at the University of Dundee.
“Our new findings add to a number of emerging treatment strategies targeting the PINK1 pathway, some that are now entering clinical trials for Parkinson’s patients this year. This work provides a framework to undertake future studies directed at finding new drug-like molecules that can target PINK1 at the TOM complex.”
Professor Dario Alessi, director of the MRC-PPU, added, “This is bold and painstaking molecular research which allows us to better understand the biology that underlies Parkinson’s disease, and provides new ideas on how PINK1-controlled Parkinson’s disease could be better diagnosed and treated, opening the door for further important research.”
However, the study also has its limitations. The research primarily used yeast cells to model human PINK1 activation, and while yeast provides a convenient and powerful system for genetic analysis, it is not identical to human cells. Thus, further studies in mammalian systems are necessary to confirm these findings and translate them into clinical applications.
“Overall, our current analysis provides insights into human PINK1 activation that will be of utility in the development of small-molecule activators as a therapeutic strategy against Parkinson’s disease,” the researchers concluded.
The study, “Mechanism of human PINK1 activation at the TOM complex in a reconstituted system,” was authored by Olawale G. Raimi, Hina Ojha, Kenneth Ehses, Verena Dederer, Sven M. Lange, Cristian Polo Rivera, Tom D. Deegan, Yinchen Chen, Melanie Wightman, Rachel Toth, Karim P. M. Labib, Sebastian Mathea, Neil Ranson, Rubén Fernández-Busnadiego, and Miratul M. K. Muqi.
