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Gene May Offer Target to Combat Parkinson’s Disease
UCLA researchers have identiﬁed a new gene involved in Parkinson’s
disease, perhaps providing a target for drugs that could one day prevent,
or even cure, the debilitating illness.
Ming Guo, MD (RES ’01, FEL ’02), PhD, associate professor of neurology
and pharmacology, and her team were one of two groups in 2006 that
ﬁrst reported that two genes, PTEN-induced putative kinase 1 (PINK1)
and parkin, act together to maintain the health of mitochondria, which
power the neurons that are important for maintaining brain health.
Mutations in these genes lead to early-onset Parkinson’s disease.
Dr. Guo’s team also showed that when the PINK1 and parkin
genes are operating correctly, they help maintain the regular shape of
healthy mitochondria and help cells eliminate damaged mitochondria.
Mouse neurons showing that loss of MUL1 in Parkinson’s disease model is detrimental to neuronal
health. (Top) Neurons stained with indicator of mitochondrial health (red) show that loss of
MUL1 in Parkinson’s disease model induces mitochondrial damage. (Bottom) Neurons visualized
with GFP showing abnormal neuronal morphology and death in loss of both MUL1 and parkin.
The accumulation of unhealthy or damaged mitochondria in neurons
and muscles ultimately results in Parkinson’s disease.
In the new study, Dr. Guo and her colleagues found that a gene
called MUL1 (also known as MULAN and MAPL) plays an important
role in mediating the pathology of the PINK1 and parkin. The study,
performed in fruit ﬂies and mice, showed that providing an extra amount
of MUL1 helps reduce the amount of damage that mutated PINK1/parkin
create in mitochondria and that inhibiting MUL1 in mutant PINK1/
parkin exacerbates the damage to the mitochondria. In addition, Dr. Guo
and her collaborators found that removing MUL1 from mouse neurons
of the parkin disease model results in unhealthy mitochondria and
degeneration of the neurons.
“We show that MUL1 dosage is key, and optimizing its function
is crucial for brain health and to ward off Parkinson’s disease,”
Dr. Guo says. “Our work proves that mitochondrial health is of central
importance to keep us from suffering from neurodegeneration. Further,
ﬁnding a drug that can enhance MUL1 function would be of great
beneﬁt to patients with Parkinson’s disease. This ﬁnding is a major
advance in research into Parkinson’s disease.”
There are several implications to this work. MUL1 appears to be a
promising drug target, “and it may constitute a new pathway regulating the
quality of mitochondria,” Dr. Guo says. She and her team plan to test their
results in more-complex organisms, hoping to understand more about
how MUL1 works. The team also will work on identifying compounds that
could speciﬁcally target MUL1 and examine whether or not mutations in
MUL1 exist in some people with inherited forms of Parkinson’s.
“MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin
and compensates for loss of PINK1/parkin,” eLife, June 4, 2014
Images: Courtesy of Dr. Ming Guo
determine whether or not they divided after
initial fetal development, but the accuracy
of this technique was debated. Others
published theories that the heart muscle
had a very-high proliferative ability; recently,
many of those papers were retracted because
colleagues were unable to replicate the data.
To address the problems of measurement,
Dr. Ardehali and his colleagues pioneered
a novel genetic approach called mosaic
analysis with double markers, or MADAM,
to directly measure for the first time heart-
cell division in a mouse model. They found
that limited, lifelong symmetric division
of cardiomyocytes, while rare, is evident in
mice, but it diminishes significantly after
the first month of life. No stem cells are
involved in this process, the researchers
said, and division of cardiomyocytes is
limited to less than 1 percent per year.
The daughter cardiomyocytes that
are the products of this rare cell division
also divide, the researchers said, though
very seldomly, which had not been shown
before. The scientists found that the
rate of cell division did not increase as
a reparative response when myocardial
infarction was induced in the mice.
“This is one of the most-convincing
and direct ways of showing that the
heart has a very limited regenerative
power,” Dr. Ardehali says. “This is a very
exciting discovery because we hope to
use this knowledge to eventually be able
to regenerate heart tissue. The goal is to
identify the molecular pathways involved
in symmetric division of cardiomyocytes
and use them to induce regeneration
to replenish heart muscle tissue after
disease or injury.”
“Existing cardiomyocytes generate
cardiomyocytes at a low rate after birth in
mice,” Proceedings of the National Academy
of Sciences, June 17, 2014