Parkinson's mutation stunts neurons

Nov 22, 2006

Mutations in a key brain protein known to underlie a form of Parkinson's disease wreaks its damage by stunting the normal growth and branching of neurons, researchers have found. They have pinpointed the malfunction of the protein made by mutant forms of the gene called LRRK2 and how it affects neurons, ultimately leading to their death.

The researchers, Asa Abeliovich and colleagues at Columbia University, said their findings could lead to animal models for studying the form of PD and ultimately to new treatments for the disease. They reported their findings in the November 22, 2006, issue of the journal Neuron, published by Cell Press.

The researchers launched their study of LRRK2 because other scientists had identified mutations in the gene in an inherited form of PD that mimics the clinical and pathological features of the common sporadic form of the disease. LRRK2 stands for "leucine-rich repeat kinase-2," which means that the LRRK2 protein is an enzyme called a kinase--a biochemical switch that activates other proteins by attaching a molecule called a phosphate to them.

In their experiments, when the researchers generated mutant forms of the enzyme, they discovered that the mutants showed higher-than-normal enzymatic kinase activity compared to the normal version. When they introduced the mutant forms into cultures of neurons, they saw a reduction in the growth and branching of the neurons. Such growth is critical for the neurons to establish and maintain connections with one another in the brain's neural circuitry. The researchers also found that cultured neurons with mutant LRRK2 enzymes showed reduced survival.

The researchers analyzed the function of the mutant proteins, establishing that it was the "triggering" kinase segment of the protein that was central to the enzyme's defective function.

The pathology of PD caused by mutated LRRK2 also includes formation of abnormal deposits, or "inclusions," in the neurons. Similarly, Abeliovich and his colleagues found that the mutant LRRK2 proteins they created also caused such inclusions in the brain cell cultures.

What's more, when the researchers introduced the mutant form of LRRK2 into the adult rat brain, they saw the same stunting of growth of dopamine-producing neurons and production of abnormal inclusions. Finally, when they introduced the mutant LRRK2 into embryonic rat brain, they saw a reduction of length and branching of neuronal wiring during brain development.

The researchers wrote that their findings offer "a useful animal model for early LRRK2-associated disease." They concluded that their techniques of introducing the mutated gene could lead to a primate model for the form of PD. "These cellular and animal models may promote the discovery of effective therapeutics for LRRK2-associated disease," they wrote.

Source: Cell Press

Explore further: Stem cells faulty in Duchenne muscular dystrophy

add to favorites email to friend print save as pdf

Related Stories

People finding their 'waze' to once-hidden streets

9 hours ago

When the people whose houses hug the narrow warren of streets paralleling the busiest urban freeway in America began to see bumper-to-bumper traffic crawling by their homes a year or so ago, they were baffled.

Identity theft victims face months of hassle

10 hours ago

As soon as Mark Kim found out his personal information was compromised in a data breach at Target last year, the 36-year-old tech worker signed up for the retailer's free credit monitoring offer so he would ...

Observers slam 'lackluster' Lima climate deal

10 hours ago

A carbon-curbing deal struck in Lima on Sunday was a watered-down compromise where national intransigence threatened the goal of a pact to save Earth's climate system, green groups said.

Your info has been hacked. Now what do you do?

10 hours ago

Criminals stole personal information from tens of millions of Americans in data breaches this past year. Of those affected, one in three may become victims of identity theft, according to research firm Javelin. ...

New Bond script stolen in Sony hack

10 hours ago

An "early version" of the screenplay for the new James Bond film was the latest victim of a massive hacking attack on Sony Pictures Entertainment, its producers said in a statement on their website Sunday.

Ag-tech could change how the world eats

15 hours ago

Investors and entrepreneurs behind some of the world's newest industries have started to put their money and tech talents into farming - the world's oldest industry - with an audacious agenda: to make sure there is enough ...

Recommended for you

Stem cells faulty in Duchenne muscular dystrophy

19 hours ago

Like human patients, mice with a form of Duchenne muscular dystrophy undergo progressive muscle degeneration and accumulate connective tissue as they age. Now, researchers at the Stanford University School of Medicine have ...

User comments : 0

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.