Scientists look to Tunisia to find new target for stopping Parkinson disease

By analyzing the DNA of people in remote Tunisian villages, researchers with the Centre for Applied Neurogenetics at the Djavad Mowafaghian Centre for Brain Health have found a gene that affects the onset of symptoms in a common but inherited form of Parkinson disease – providing a potentially useful target in the search for a better treatment.

Variations in a gene called Dynamin-3 may delay the appearance of symptoms by a median of 12.5 years, according to the research published this week in Lancet Neurology.

Parkinson disease results from the depletion of cells that produce the neurotransmitter dopamine. Nobody yet knows why those cells die, and no drugs can stop it. Decreasing levels of dopamine leads to tremors, slowness or stiffness, impaired balance, often accompanied by fatigue, soft speech, constipation and sleep disturbances. The main drug treatment, levodopa, doesn’t control or slow the disease, but alleviates the symptoms.

Most cases of Parkinson disease don’t have an identifiable cause. Some cases, however, can be traced to specific genetic mutations.

Dr. Matthew Farrer, Canada Excellence Research Chair in Neurogenetics and Translational Neuroscience, previously discovered one such mutation, called LRRK2 G2019S, among inhabitants of Norwegian fishing villages. However, the same mutation is far more frequently found among Berbers, an ethnic group of perhaps 50 million people in North Africa and Eastern Mediterranean. The mutation also is found at relatively high frequency among Ashkenazi Jews.

Dr. Farrer collaborated with researchers in Tunisia to find Berbers with Parkinson disease with that mutation. With the help of local neurologists, the team collected blood samples and clinical data from hundreds affected and unaffected carriers. By analyzing those samples, they were able to pinpoint genetic variations in Dynamin-3 as a key factor in the age of disease onset.

The gene encodes a protein required to absorb, transport and recycle proteins that are crucial in sending and receiving signals from one brain cell to another.

“Dynamin-3 seems to control disease onset by helping the brain adapt to subtle but chronic problems in neurotransmission caused by the LRRK2 G2019S mutation,” said Dr. Farrer. “Since problems with neurotransmission are a common underlying cause of many forms of Parkinson disease, Dynamin-3 gives us much-needed molecular insight to help develop drugs to halt the disease’s progression.”

“The latest advances in gene sequencing technology are not only leading to the discovery of disease-causing mutations, but also revealing a surprisingly large number of people who have such mutations, and yet don’t develop the disease,” says lead author Joanne Trinh, a graduate student who works in Dr. Farrer’s lab. “Those people, and how their biology compensates, give us important clues to protect others from neurodegenerative disease.”