Parkinson’s discovery at odds with prevalent hypothesis, finds serotonin increase in prodromal PD

By the time a person with Parkinson’s disease (PD) receives a diagnosis, they have already lost a substantial amount of their brain dopamine and a lesser extent of brain serotonin. A new international study looked at people with an inherited gene mutation linked to PD prior to or at the earliest stages of disease onset to determine if a reduction in serotonin is detectable prior to diagnosis. Instead, what they found was that serotonin had actually increased in those with the genetic abnormality.

Led by Dr. Jon Stoessl, co-director of the Djavad Mowafaghian Centre for Brain Health and Head of the Division of Neurology in the UBC Faculty of Medicine, the researchers found that in patients with LRRK2, the gene responsible for an inherited form of PD, there is an increase in serotonin nerve terminals, possibly reflecting the brain’s attempts to compensate for the decrease in dopamine associated with PD.

“We think this compensation may be a good thing,” explains Dr. Stoessl, “but we’re trying to understand what it costs in terms of function, not only before the disease manifests, but also in terms of response to treatment.”

The current, prevalent hypothesis, proposed by German researcher Dr. Heiko Braak, theorizes that the earliest signs of PD begin in the olfactory region of the brain, and in the lower brainstem, before traveling upwards through the brainstem, ultimately affecting the nerve cells in the midbrain responsible for dopamine production. Loss of dopamine contributes to a loss of movement ability and altered reward signaling, both symptoms of Parkinson’s disease. Levodopa, the leading drug treatment for PD, is used to replace the missing dopamine, but does so imperfectly, as its release is not regulated the same as in the normal brain. When serotonin nerve fibres take over the production of dopamine from levodopa, this may result in pathological patterns of release and could potentially lead to abnormal movements and impulsive behaviours.

The study, funded by the Michael J. Fox Foundation and published in Lancet Neurology, looked at a large cohort of people with both the inherited and sporadic forms of the disease. Patients participated from around the world – a major logistical undertaking – and were evaluated via positron emission tomography (PET) to determine if dopamine and serotonin system changes were similar in those with the mutation and those without. In general, the loss of dopamine progresses the same whether a patient has sporadic or familial PD, once the disease starts. The difference is in how those with the mutation – the familial form of the disease – expressed higher levels of serotonin nerve terminal prior to disease onset.

“This discovery gives us particular insight into the mechanism of the gene mutation, and suggests that we may be able to predict whether people with the mutation are more prone to problems with involuntary movements and impulse control on standard medication,” says Dr. Stoessl. “In the long term, these changes may contribute to differences in response to treatment in those with the inherited form of PD.”

First author on the paper, Dr. Daryl Wile, was a Clinical Fellow at UBC during the research, and was supported by a grant from Parkinson Canada.

The mutation in the LRRK2 gene was originally discovered in collaboration between researchers at UBC and at the Mayo Clinic in Florida, including Dr. Matt Farrer who was based at the Mayo Clinic at the time. The genome mapping that spurred the LRRK2 discovery was part of an international collaboration, and was reported in Neuron in 2004.