Scientists probing molecular origins of Parkinson’s disease highlight two proteins

11 Aug

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?

older lady seated with walking stick

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

Parkinson’s disease.

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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