Not guility: Parkinson and protein phosphorylation

August 26, 2013, Ecole Polytechnique Federale de Lausanne

Clues left at the scene of the crime don't always point to the guilty party, as EPFL researchers investigating Parkinson's disease have discovered. It is generally accepted that the disease is aggravated when a specific protein is transformed by an enzyme. The EPFL neuroscientists were able to show that, on the contrary, this transformation tends to protect against the progression of the disease. This surprising conclusion could radically change therapeutic approaches that are currently being developed by pharmaceutical companies. The research is to appear in an article in the Proceedings of the National Academy of Sciences (PNAS).

Parkinson's disease is characterized by the accumulation of a protein known as alpha-synuclein in the brain. If too much of it is produced or if it's not eliminated properly, it then aggregates into small inside the , eventually killing them. Several years ago scientists discovered that these aggregated had undergone a transformation known as "phosphorylation"—a process in which an enzyme adds an extra chemical element to a protein, thus modifying its properties.

The investigators' conclusion that the enzyme's activity could be responsible for the disease seems eminently reasonable. If phosphorylation and protein aggregation go hand in hand, then it makes sense that one should cause the other. This is the assumption that researchers and made as they tried to reduce the phosphorylation by deactivating an enzyme involved in the process. But they have been following a false lead, as the EPFL team was able to show.

The scientists even discovered that the phosphorylation of the protein has positive effects. On the one hand, it considerably reduces the toxic aggregation of the protein, and on the other, it helps the cell eliminate the protein. "The two phenomena are undoubtedly related, and together could play a role in the reduction of alpha-synuclein toxicity, but we don't yet understand the impact of both processes at each stage of the disease," explains neurobiologist Abid Oueslati, first author on the study.

Going back to the beginning

To reach this conclusion, the biologists had to explore the initial disease conditions. They injected into rat neurons what were thought to be the elements needed to trigger the disease: an overexpression of alpha-synuclein and the enzyme that phosphorylates it (PLK2).

To their surprise, the group of animals subjected to both of the parameters—overproduction of the protein and phosphorylation—lost nearly 70% fewer neurons than another group in which only the protein was overexpressed. Consequently, they had fewer lesions, and less Parkinson symptoms.

"We owe this discovery to unique tools that we developed, in collaboration with the Aebischer group, in order to study the effect of this transformation at the molecular level. ," explains Hilal Lashuel, who directed the study. Our study revealed the limitations of the most commonly used approach, which uses genetic mutations to mimic this process.

Lashuel thinks it is highly probable that the phosphorylation of the proteins takes place after they are aggregated, that is to say once the disease is already established. Or it could be a defense mechanism of the neurons, an attempt to try and slow down the progression of the disease from the beginning.

The scientists' research opens doors for the development of future drug therapies. "The lesson we learned from this research is that everything you find at the scene of a crime is not necessarily involved in the crime. By remaining fixated on that assumption, we may lose sight of the bigger picture."

Explore further: Study shows how Parkinson's disease protein acts like a virus

More information: Polo-like kinase 2 regulates selective autophagic ?-synuclein clearance and suppresses its toxicity in vivo , www.pnas.org/cgi/doi/10.1073/pnas.1309991110

Related Stories

Study shows how Parkinson's disease protein acts like a virus

April 25, 2013
A protein known to be a key player in the development of Parkinson's disease is able to enter and harm cells in the same way that viruses do, according to a Loyola University Chicago Stritch School of Medicine study.

SUMO defeats protein aggregates that typify Parkinson's disease

July 11, 2011
A small protein called SUMO might prevent the protein aggregations that typify Parkinson's disease (PD), according to a new study in the July 11, 2011, issue of The Journal of Cell Biology.

Shape-shifting disease proteins may explain variable appearance of neurodegenerative diseases

July 3, 2013
Neurodegenerative diseases are not all alike. Two individuals suffering from the same disease may experience very different age of onset, symptoms, severity, and constellation of impairments, as well as different rates of ...

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.

New animal model gives insights into mechanisms of Parkinson's disease pathogenesis

May 24, 2013
In Parkinson's disease, the protein "alpha-synuclein" aggregates and accumulates within neurons. Specific areas of the brain become progressively affected as the disease develops and advances. The mechanism underlying this ...

Recommended for you

Link between tuberculosis and Parkinson's disease discovered

May 22, 2018
The mechanism our immune cells use to clear bacterial infections like tuberculosis (TB) might also be implicated in Parkinson's disease, according to a new collaborative study led by scientists from the Francis Crick Institute ...

Link between IBD and Parkinson's might allow doctors to slow down condition

May 21, 2018
Doctors may be able to modify or slow down the progress of the neurological condition Parkinson's disease in the future by spotting signs of it in patients with inflammatory bowel disease (IBD), suggest a study published ...

Untangling brain neuron dysfunction in Parkinson's disease and dementia with Lewy bodies

May 10, 2018
A decay of brain function is a hallmark of Parkinson's disease and dementia with Lewy bodies, or DLB. Specifically, cognitive dysfunction defines DLB, and nearly eight of every 10 Parkinson's patients develop dementia.

Diverse Parkinson's-related disorders may stem from different strains of same protein

May 9, 2018
Different Parkinson's-related brain disorders, called synucleionpathies, are characterized by misfolded proteins embedded in cells. Researchers in the Perelman School of Medicine at the University of Pennsylvania found that ...

New study sheds light on the complex dynamics of Parkinson's disease

May 3, 2018
Parkinson's disease affects around 10 million people worldwide, yet exactly how the disease and treatments for its symptoms work remains a bit mysterious. Now, Stanford researchers have tested a seminal theory of Parkinson's ...

Researchers find that lipid accumulation in the brain may be an early sign of Parkinson's disease

April 29, 2018
A collaborative team of researchers at McLean Hospital, a Harvard Medical School affiliate, and Oxford University has found that elevated levels of certain types of lipids (fat molecules) in the brain may be an early sign ...

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.