Research provides new understanding of Parkinson's and Alzheimer's disease and opens path to treatment

October 26, 2016

A team of scientists at Baylor College of Medicine and Texas Children's Hospital has discovered that in three separate laboratory models, the protein TRIM28 can promote the accumulation of two key proteins that drive the development of Parkinson's, Alzheimer's and related diseases. The discovery, which appears in eLife, offers a new understanding of these diseases and possible opportunities for drug development.

"TRIM28 is a that plays an essential role during embryonic development," said senior author Dr. Huda Zoghbi, professor of molecular and and of pediatrics - neurology and developmental neuroscience at Baylor and director of the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital. "Here we have discovered that it can also regulate proteins that contribute to the development of Alzheimer's and Parkinson's disease."

Neurodegenerative diseases such as Alzheimer's and Parkinson's disease are driven by the accumulation of proteins to levels that are toxic to the brain. Two of these proteins are alpha-synuclein, which accumulates in Parkinson's disease, and tau, which drives Alzheimer's disease.

"A number of patients with Parkinson's disease also present with symptoms of dementia. In these cases the brains show accumulation of both alpha-synuclein and tau," said first author Dr. Maxime Rousseaux, postdoctoral associate in the Zoghbi lab. "And there is a subset of patients with dementias that are driven by tau, but where you also find alpha-synuclein accumulation."

This medical evidence inspired the researchers to investigate why of all the proteins that accumulate in the brain in these diseases, tau and alpha-synuclein are the two that often are found together in Parkinson's and Alzheimer's.

To study this, the scientists carried out two sets of screening experiments. They carried out screening and validation in human cells in the Zoghbi lab, and in fruit flies in the laboratory of Dr. Juan Botas, professor of molecular and human genetics and of molecular and cellular biology at Baylor. In one set of experiments they screened for genes that alter the levels of alpha-synuclein and in another they screened for genes that alter the levels of tau. They found a number of genes that can regulate either tau or alpha-synuclein, but only one strong regulator of both, TRIM28.

"When we reduced the activity of TRIM28 by 50 percent, the levels of tau and alpha-synuclein decreased and the damage to the cells was markedly reduced," said Zoghbi, who also is an investigator at the Howard Hughes Medical Institute.

To find clues about the mechanism by which TRIM28 brings tau and alpha-synuclein together, the scientists asked what would happen to these molecules if they increased the amount of TRIM28 in the cells.

"We worked with two mouse models – one of alpha-synuclein accumulation and one of tau accumulation – and overexpressed TRIM28 before the animals showed further accumulation of either protein or symptoms of disease," said Rousseaux. "We observed that overexpressing TRIM28 accelerated the accumulation of the proteins in the respective animal models."

Further experiments showed that tau and alpha-synuclein form complexes with TRIM28 and that these complexes stabilize the proteins. Using brain cells grown in the lab, the scientists revealed that the complexes accumulate preferentially in the nucleus of the cells and are toxic.

Collaborating with a team at Johns Hopkins University School of Medicine, they also discovered that TRIM28 was linked to the accumulation of tau and alpha-synuclein in the nucleus in postmortem brain tissue from individuals who suffered from Parkinson's disease and related disorders.

"Our work shows that by reducing the activity of TRIM28 we can clearly reduce the accumulation of tau and alpha-synuclein in fruit flies and mouse models of the disease," said Zoghbi. "These results encourage us to consider the possibility of developing drugs that could reduce the levels of TRIM28 to help prevent the development of Alzheimer's, Parkinson's and related diseases."

Explore further: Study reveals potential new strategy to prevent Alzheimer's disease

Related Stories

Study reveals potential new strategy to prevent Alzheimer's disease

October 7, 2016
Taking a pill that prevents the accumulation of toxic molecules in the brain might someday help prevent or delay Alzheimer's disease, according to scientists at Baylor College of Medicine, Texas Children's Hospital and Johns ...

Parkinson's disease protein plays vital 'marshalling' role in healthy brains

September 19, 2016
Researchers have uncovered the normal function of a protein associated with Parkinson's disease, giving clues about what happens when it malfunctions.

How Parkinson's disease starts and spreads

April 16, 2012
Injection of a small amount of clumped protein triggers a cascade of events leading to a Parkinson's-like disease in mice, according to an article published online this week in the Journal of Experimental Medicine.

Bath scientists find clues to dementia and Parkinson's

November 7, 2013
A research team from our Department of Biology and Biochemistry has identified a possible target to reduce the levels of a protein called alpha-synuclein – linked to both Parkinson's disease and dementia with Lewy bodies.

Discovery may lead to a treatment to slow Parkinson's disease

July 19, 2016
Using a robust model for Parkinson's disease, University of Alabama at Birmingham researchers and colleagues have discovered an interaction in neurons that contributes to Parkinson's disease, and they have shown that drugs ...

New model recreates early spread of Parkinson's disease in the brain

August 8, 2016
They're two of the biggest mysteries in Parkinson's disease research—where does the disease start? And how can it be stopped early in the process?

Recommended for you

Critical toxic species behind Parkinson's disease is glimpsed at work for the first time

December 14, 2017
Researchers have glimpsed how the toxic protein clusters that are associated with Parkinson's Disease disrupt the membranes of healthy brain cells, creating defects in the cell walls and eventually causing a series of events ...

Tapeworm drug could lead the fight against Parkinson's disease

December 12, 2017
Researchers at Cardiff University, in collaboration with the University of Dundee, have identified a drug molecule within a medicine used to treat tapeworm infections which could lead to new treatments for patients with Parkinson's ...

High-intensity exercise delays Parkinson's progression

December 11, 2017
High-intensity exercise three times a week is safe for individuals with early-stage Parkinson's disease and decreases worsening of motor symptoms, according to a new phase 2, multi-site trial led by Northwestern Medicine ...

Changes in diet may improve life expectancy in Parkinson's patients

November 24, 2017
New research from the University of Aberdeen shows that weight loss in people with Parkinson's disease leads to decreased life expectancy, increased risk of dementia and more dependency on care.

Good cells gone bad: Scientists discover PINK-SNO

November 21, 2017
A new study from The Scripps Research Institute (TSRI) is the first to show precisely how a process in nerve cells called the S-nitrosylation (SNO) reaction—which can be caused by aging, pesticides and pollution—may contribute ...

Genetic defects in the cell's 'waste disposal system' linked to Parkinson's disease

November 14, 2017
An international study has shed new light on the genetic factors associated with Parkinson's disease, pointing at a group of lysosomal storage disorder genes as potential major contributors to the onset and progression of ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.