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Parkinson's breakthrough: New disease-causing mechanism found

Published 2 Oct 2017

Parkinson's breakthrough: New disease-causing mechanism found

A new study led by scientists in South Korea and Singapore "overturns three decades of consensus" on what causes Parkinson's disease symptoms.

A study recently published in the journal Neuron sheds new light on the disease-causing mechanism behind Parkinson's.

Broadly speaking, Parkinson's disease is known to be caused by insufficient levels of the neurotransmitter dopamine. In more detail, however, it is not precisely known what causes the motor problems - including tremor, stiffness, and the inability to control movements - that characterize this low-dopamine condition.

Voluntary movement is known to be regulated by a brain region called the basal ganglia. The basal ganglia modulates locomotion by shifting between instructions to trigger motion and instructions to suppress it.

Achieving the delicate balance between these two sets of instructions results in smooth motions.

Because a low level of the dopamine neurotransmitter more strongly suppresses movement and low dopamine characterizes Parkinson's disease, researchers have long believed that suppression induced by a lack of dopamine causes the motor dysfunction in Parkinson's.

The new study, however, uses cutting-edge technology to challenge this belief.

The researchers were co-led by Prof. Daesoo Kim, from the Department of Biological Sciences at the Korea Advanced Institute of Science & Technology in Daejeon, South Korea, and Prof. George Augustine, from the Lee Kong Chian School of Medicine in Singapore.

Study yields 'breakthrough' findings

Using optogenetics - a technique wherein neurons are genetically modified to respond to light, enabling the researchers to track and control the behavior of the cells - the scientists stimulated inhibitory basal ganglia inputs. In other words, they intensified the motor suppression instructions.

However, they found that this made ventrolateral thalamic neurons - which are involved in motor control - hyperactive.

This hyperactivity seemed to cause muscular rigidity and contractions in the rodents - symptoms similar to the hallmark motor symptoms in Parkinson's disease.

As the authors explain, this is the phenomenon called "rebound firing," which seems to be triggered by intensifying inhibitory basal ganglia inputs.

Prof. Kim and team tested the role of this phenomenon by genetically engineering mice to lack dopamine and inhibiting rebound firing to see what effects it would have on Parkinson's disease motor symptoms.
Rebound firing was inhibited by genetically interfering to reduce the number of ventrolateral thalamic neurons.

Surprisingly, mice with abnormally low levels of dopamine but no rebound firing displayed normal movement and no Parkinson's disease symptoms.

"In a low dopamine state," the authors say, "the number of [ventrolateral thalamic] neurons showing post-inhibitory firing increases, while reducing the number of active [ventrolateral thalamic] neurons [by inhibiting basal ganglia] input, effectively prevents Parkinson disease-like motor symptoms."

"Thus, [basal ganglia] inhibitory input generates excitatory motor signals in the thalamus and, in excess, promotes PD-like [Parkinson's disease-like] motor abnormalities," they conclude.

"This study," says Prof. Daesoo Kim, as he comments on the significance of the findings, "overturns three decades of consensus on the provenance of Parkinsonian symptoms."

First study author Dr. Jeongjin Kim says, "The therapeutic implications of this study for the treatment of Parkinsonian symptoms are profound. It may soon become possible to remedy movement disorders without using L-Dopa, a precursor to dopamine."

MedicalNewsToday.com

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