Unlocking the Keys to Parkinson’s Disease

Parkinson’s disease (PD) is a debilitating movement disorder that affects more than 10 million people worldwide. It is well known that the lack of dopamine, a brain neuromodulator triggers the disease. However, it is hardly known what causes debilitating motor abnormalities such as tremors and loss of voluntary movement which plague PD patients.

Professor Daesoo Kim of the Department of Biological Sciences identified a new mechanism that is an underlying cause of its hallmark symptoms of Parkinson disease in collaboration with a research team from the Nanyang Technological University. The discovery will help to alleviate the motor problems suffered by Parkinson patients. The research led by Professor Kim and Dr. George Augustine of the Lee Kong Chian School of Medicine at NTU was published in Neuron on August 30. Dr. Jeongjin Kim, former postdoctoral fellow at KAIST who now works at the Korea Institute of Science and Technology, is the lead author.

The basal ganglia is a brain structure that controls complex movements. During low dopamine states, the basal ganglia more strongly inhibit their target neurons. For the past three decades, scientists have assumed that this stronger inhibition caused the motor problems of PD patients. To test this assumption, the researchers used optogenetic technology to directly activate basal ganglia inhibitory output and then examined the response of target neurons in the thalamus, a part of brain also involved with movement.

Surprisingly, the target neurons in the thalamus exhibited a paradoxical increase in activity in response to the inhibition. This rebound excitation produced aberrant muscular rigidity and tremors that are very similar to the symptoms of PD patients. Eliminating this rebound firing caused the motor symptoms to be completed cured in an animal model of PD, proving that the rebound firing causes the motor problems experienced by PD patients.

Professor Kim sees the study overturning three decades of consensus on the provenance of Parkinsonian symptoms. The lead author, Dr. Kim, remarked, “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 dopamine.” Dr. Augustine at NTU added, “This is a big breakthrough, both for understanding how the brain normally controls the movement of our body and how this control goes awry during PD and related dopamine-deficiency disorders. Most importantly, our work opens up promising new avenues for alleviating the suffering of PD patients.”

Parkinson's Disease
Figure abstract: Inhibitory inputs from the basal ganglia inhibit thalamic neurons (upper). In low-dopamine states, like PD, rebound firing follows inhibition and causes movement disorders (middle). The inhibition of rebound firing alleviates PD-like symptoms in a mouse model of PD.

Source : KAIST