From left to right, Professor David Komander, Dr. Nicholas Kirk, Dr. Sylvie Callegari, and Dr. Alisa Glukhova, the research team behind this study.
- The exact cause of Parkinson’s disease remains
unknown; however, researchers know some genetic factors contribute to the
condition, such as a mutation in the PINK1 gene.
- A new study for the first time explains what
human PINK1 looks
like and how it is activated.
- Researchers believe these findings may help one
day lead to new treatment options for Parkinson’s disease.
Researchers estimate that
about 10 million people globally
live with Parkinson’s disease —
a neurological condition that affects movement.
While the exact cause of
Parkinson’s disease is still unknown, past studies show that a combination of
both environmental and genetic factors contribute to the
condition.
For instance, scientists have
discovered that having certain genes may increase a person’s risk for
developing Parkinson’s disease, such as a mutation in the PINK1 (PTEN-induced putative
kinase 1) gene.
Now, a new study recently published in the journal Science for
the first time explains what human PINK1 looks
like and how it is activated.
Researchers believe these
findings may help one day lead to new treatment options for Parkinson’s
disease.
What does PINK1 do
in the body?
PINK1 plays an important role in the body as the
protein it expresses helps protect mitochondria — the cellular energy sources
— from harm, and leads their removal from the body when they do become damaged
over time.
“[The] PINK1 [protein] acts
as a beacon for damaged mitochondria, famously known as the ‘powerhouse of the
cell’,” Sylvie Callegari, PhD,
senior research officer in the Ubiquitin Signalling Division at The Walter and
Eliza Hall Institute of Medical Research in Australia, and both first and
corresponding author of this study told Medical
News Today.
“PINK1 senses this damage and docks to the surface
of mitochondria. Once positioned on the mitochondrial surface, PINK1 becomes
active and seeks out a small protein known as
“When damaged mitochondria
are not cleaned up, they release toxins, which kill cells,” she continued.
“Brain cells, such as neurons, which require a lot of energy and have
a lot of mitochondria are particularly sensitive to mitochondrial toxicity and
are more likely to die. The death of neuronal cells in the brain is what causes
Parkinson’s disease.”
Mutated
PINK1 leads to neuronal cell death
Callegari
said that up until now, one of the main obstacles that has prevented
researchers from seeing what PINK1 looks like was that there is not very much
PINK1 in the cell.
“Until now, scientists had
been studying insect PINK1 because it is possible to produce it in large
amounts, and by visualizing insect PINK1, we were able to decipher how it can
be activated,” she explained.
“However, we were never
able to see how PINK1 docks to the mitochondrial surface, which is the
important step that precedes its activation. To get around this problem, we used very large amounts
of cells (nearly 10L) to get enough human PINK1 that we could then use for
visualization using
Callegari and her team discovered there are four
main steps to how PINK1 works: Sensing mitochondrial damage, attaching to the
damaged mitochondria, tagging ubiquitin, and then ubiquitin links to a protein
called Parkin to “recycle” the injured mitochondria.
“PINK1 is special because
it can alter the ubiquitin tag by placing an additional marker on it — it
basically tags the tag,” Callegari said. “This alteration is a very specific
signal that initiates the disposal of the entire mitochondria.”
HOW
PINK1 CAUSES PARKINSON’S
“When PINK1 is mutated, it cannot perform its
signaling function, and so mitochondria are not effectively cleaned up.
Defective mitochondria are toxic to cells, resulting in cell death. The death
of neuronal cells in the brain causes Parkinson’s disease.”— Sylvie Callegari,
PhD
‘Big leap
closer’ to new Parkinson’s disease therapies
Callegari
believes their findings bring us a big leap closer to developing therapies for
Parkinson’s disease.
“Ideally, we want to design
a drug that makes PINK1 more active, but without the ability to see PINK1, it
is very hard to develop a drug to do this,” she explained. “Now that we can see
PINK1, we have the blueprint that we need to improve its activity.”
“There are currently some
drugs in the pipeline that are believed to increase the activity of PINK1, but
without ever seeing where or how these drugs interact with PINK1, we don’t have
a complete understanding of how they work. We plan to use our approach to
visualize these drugs in association with PINK1 to understand how they work.
Furthermore, we will also use our PINK1 model to design new drugs that increase
PINK1 activity.”— Sylvie Callegari, PhD
New targeted therapies based on PINK1
MNT spoke with Daniel Truong, MD, neurologist and medical
director of the Truong Neuroscience Institute at MemorialCare Orange Coast
Medical Center in Fountain Valley, CA, and editor-in-chief of the
Journal of Clinical Parkinsonism and Related Disorders, about this study.
“As a physician who treats
patients with Parkinson’s disease, the recent elucidation of the human PINK1
protein structure bound to mitochondria is a significant and encouraging
development,” Truong commented.
“Mutations in the PINK1 gene
have been linked to early-onset Parkinson’s disease. By resolving the structure
of PINK1, researchers have provided deeper insights into its function and how
its dysfunction can lead to neurodegeneration,” he added.
“Understanding the
structural configuration of PINK1 will open avenues for developing targeted
therapies aimed at modulating its activity. This could lead to interventions
that enhance mitochondrial quality control mechanisms, potentially slowing or
halting disease progression. With the understanding of the structural blueprint
of PINK1, pharmaceutical research can focus on designing molecules that
interact precisely with this protein leading to more effective treatments with
fewer side effects.”— Daniel Truong, MD
Translating
findings into treatment will require more research
MNT also spoke with two neurologists from Hackensack
Meridian in New Jersey about this research.
Rocco DiPaola, MD,
neurologist and movement disorder specialist at Hackensack Meridian
Neuroscience Institute at the Jersey Shore University Medical Center commented
that this study is another positive step in uncovering and understanding the
mechanisms involved in hereditary forms of Parkinsonism.
“It is important to continue to look for new ways to
treat Parkinson’s disease, as current therapies have their limitations,
primarily addressing
Umer Akbar, MD,
neurologist and director of the Movement Disorder Center in the Department of
Neurology and Hackensack Meridian Neuroscience Institute at Hackensack
University Medical Center, said that while this discovery provides crucial
foundational knowledge, but translating this knowledge to find a cure or an
effective treatment will require further research.
“Drug development is a long
and complex process, and many promising drug candidates fail in clinical
trials. However, this discovery undoubtedly removes a major obstacle and
significantly increases the chances of developing effective therapies for
Parkinson’s disease in the future. It provides a much-needed roadmap for future
research and drug development efforts.”— Umer Akbar, MD
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