Researchers grappling to understand what happens inside brain cells of
people with Parkinson’s disease are baffled by a mystery that plays out as the
disease progresses. Why is it that one group of neurons decays while a similar
group nearby remains unscathed?
research discovers two proteins that appear to protect the brain cells most
affected by Parkinson’s disease.
Answering this question could lead to new ways of treating a devastating – and
currently incurable – brain-wasting disease that gradually erodes the ability to
walk, talk, and live an independent life.
One answer is offered in a study published in Nature Neuroscience.
There, a team from The Rockefeller University and Columbia University, both in New
York, NY, describes finding two proteins that may play a key role in the
progression of Parkinson’s disease.
The two proteins – SATB1 and ZDHHC2 – appear to protect the brain
cells most affected by Parkinson’s disease. When the proteins become less
active, the disease sets in.
Scientists believe the causes of Parkinson’s disease center around what are
called dopaminergic neurons. These cells release the messenger molecule dopamine, a
chemical that is important for control of movement.
The dopamine-releasing cells most affected by Parkinson’s disease are located in
a midbrain region called the substantia nigra pars compacta (SNpc). As the disease
progresses, these cells gradually deteriorate and die.
The researchers – whose study focuses on molecular changes in dopamine-releasing
cells – suggest their discovery could lead to new targets for drugs that slow the
progression of Parkinson’s disease.
Researchers searched ‘translatome’ as opposed to genome
The study is also significant for another reason – the molecular searching
method that the team used to find the two proteins.
Usually, when scientists want to look for molecular changes that affect disease,
they use genetic sequencing to create a profile of the variations in gene
But gene expression profiling is not a very useful tool when you are trying to
identify the molecular changes that occur in a particular type of cell and focus on
the really important ones.
Also, genes do not act in a straightforward manner – they also regulate each
other. There are master regulator genes that act as control dials, turning other
genes on and off, or up and down. Gene expression profiling does not easily tell
you about the molecular changes that arise from gene expression.
To overcome this difficulty, the team adapted a method that some of the
members had already been working on – one that searches the “translatome” as
opposed to the genome – to find the proteins involved in communicating changes
arising from master regulator genes.
The translatome is the complete collection of messenger molecules that are
involved with translating genetic information from DNA and carrying it to sites
where proteins are made inside cells.
With genetically engineered mice, the team captured the genetic messages being
translated into proteins in dopaminergic neurons in the mice’s midbrain region.
They then compared the interactions of regulator genes with their target genes
in the mouse brain, and used this map to interpret the changes they found between
normal mice and those with Parkinson’s-like symptoms.
Senior author Paul Greengard, a neuroscience professor who heads a Rockefeller
lab that specializes in investigating molecular activity in nerve cells, says:
“Within a dying nerve cell, the levels of hundreds of proteins change. Some of
these shifts are consequences, others are causes. We set out to find which cause
cell death among neurons.”
Discovery explains why one group of dopamine cells is more affected
Their new approach helped the team find two of the so-called master regulatory
molecules. Prof. Greengard says the discovery offers an “unexpected explanation as
to why one population of neurons degenerates in Parkinson’s, while similar
neighbors do not suffer from the same degree of degeneration.”
While the dopamine-producing neurons of the SNpc are the ones most affected by
Parkinson’s disease, there is another group of dopamine-producing neurons in
another region called the ventral tegmental area (VTA) that is less affected.
The team found that the two proteins SATB1 and ZDHHC2 are more abundant
in the dopaminergic neurons in the SNpc than in the VTA.
When the researchers reduced the abundance of these molecules in the brains of
normal mice, they observed it was followed by rapid degeneration like that seen in
The team believes conventional gene expression profiling would not have been
able to identify the two proteins as key protective factors. Even though they
continue to be expressed in the neurons, their regulatory activity drops off and
they no longer stimulate their target genes, says first author Lars Brichta, a
senior research associate in Greengard’s lab, who adds:
“We later found similar changes in activity in the brains of
Parkinson’s patients, particularly those in the early stages.”
The findings also challenge current thinking about the molecular origins of
Parkinson’s disease, where it is thought that the VTA neurons are protected in some
way by the decay seen in neurons of the SNpc. But, Greengard asserts:
“In an unexpected contradiction to current models, the proteins we found protect
the SNpc. Because dopamine and its metabolites can be toxic, we can speculate that,
in the course of evolution, SATB1 and ZDHHC2 arose to protect this particular set
of sensitive neurons from cell death.”
As well as opening a route to new treatments for Parkinson’s disease, the team
believes their translatome approach may also be useful in the study of other
neurodegenerative diseases such as Alzheimer’s disease, amyotrophic lateral
sclerosis (ALS), spinal muscular atrophy, and Huntington’s disease.
Meanwhile, Medical News Today recently learned that a liver disease drug could slow Parkinson’s disease.
A paper in the journal Neurology, describes how ursodeoxycholic acid
(UDCA) – a drug that has long been used to treat liver disease – has beneficial
effects on fruit fly nerve cells with mutations in the LRRK2 gene, the most common
inherited cause of Parkinson’s disease.
Written by Catharine Paddock PhD
Copyright: Medical News Today
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