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Researchers at the WEHI Parkinson’s Disease Research Centre have made significant progress in understanding Parkinson’s disease, addressing a long-standing enigma that may lead to the creation of new therapies for this condition.
Identified over two decades ago, PINK1 is a protein associated with Parkinson’s disease, which is recognized as the fastest-growing neurodegenerative disorder globally. Despite its long-standing link to the disease, the structural details of human PINK1 and its interactions with damaged mitochondria remained unknown until now.
In a groundbreaking study published in Science, scientists unraveled the structure of human PINK1 attached to mitochondria, a development that could facilitate the discovery of novel treatments for a disease that currently has no cure.
At a glance
The research published in Science signifies a major advancement in Parkinson’s research, offering hope for accelerated drug development aimed at halting the disease’s progression.
Parkinson’s disease is notoriously difficult to diagnose, often taking many years or even decades. While it is commonly associated with motor symptoms like tremors, it encompasses nearly 40 different symptoms, including cognitive decline, issues with speech, and difficulties with vision and body temperature regulation.
In Australia alone, over 200,000 individuals are living with Parkinson’s disease, with approximately 10% to 20% diagnosed with Young Onset Parkinson’s, defined by symptoms occurring before the age of fifty. The financial burden of Parkinson’s on Australia’s healthcare system is significant, exceeding $10 billion annually.
Breakthrough after decades of research
Mitochondria are essential for cellular energy production in all living organisms, with energy-intensive cells housing numerous mitochondria. The PARK6 gene is responsible for coding the PINK1 protein, which plays a critical role in detecting and removing damaged mitochondria to promote cell health.
In a healthy individual, when mitochondrial damage occurs, PINK1 accumulates on the membranes of the affected mitochondria, signaling via a small protein called ubiquitin that these mitochondria should be destroyed. A unique signal from mutated PINK1 leads to the accumulation of damaged mitochondria within cells, contributing to the pathology of Parkinson’s disease, particularly in cases of Young Onset Parkinson’s.
Despite the established connection between PINK1 and Parkinson’s, the precise structural aspects of PINK1 and its method of attachment to mitochondria had remained elusive until this recent study.
Professor David Komander, head of the Ubiquitin Signaling Division at WEHI and a corresponding author of the study, hailed the unlocking of PINK1’s structure as a pivotal achievement in Parkinson’s research. “It’s remarkable to finally visualize PINK1 and comprehend its binding mechanism to mitochondria,” he stated. “This structure unveils multiple potential modifications to enhance PINK1 function, which could significantly impact the lives of those affected by Parkinson’s.”
Hope for future treatments
Dr. Sylvie Callegari, a senior researcher at WEHI and the lead author of the study, described PINK1’s functioning in four distinct steps, with the initial stages finally observed for the first time. Initially, PINK1 detects mitochondrial damage; it then attaches itself to the impaired mitochondria and tags them with ubiquitin, which subsequently connects to another protein known as Parkin, ultimately facilitating the recycling of damaged mitochondria.
“We’ve achieved a landmark by observing human PINK1 attached to damaged mitochondria,” Dr. Callegari noted. “This discovery has revealed an unexpected variety of proteins that create the docking site. Additionally, we have established how mutations found in Parkinson’s patients influence PINK1 activity.”
While the concept of targeting PINK1 for therapeutic interventions has been proposed for years, the lack of structural understanding has hindered progress. The research team aims to leverage this newfound knowledge to develop a drug that could slow or halt the progression of Parkinson’s disease in individuals with PINK1 mutations.
The link between PINK1 and Parkinson’s
A defining characteristic of Parkinson’s disease is the death of brain cells. The human body loses and replaces around 50 million cells each minute; however, brain cells are unique in their limited capacity for replacement upon death.
When mitochondria become damaged, they fail to produce energy and can release harmful toxins into the cells. In healthy individuals, dysfunctional cells are disposed of through a cellular process known as mitophagy. In individuals with Parkinson’s disease who possess PINK1 mutations, this process is compromised, leading to an accumulation of toxins that ultimately results in cell death. Given the high energy demands of brain cells, they are particularly vulnerable to mitochondrial damage.
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