Brainstem Mitochondrial DNA Changes Found In Parkinson’s Disease

Patients with Parkinson’s disease have more errors in the mitochondrial DNA within the brainstem, leading to increased cell death in that area, a new study has found. The researchers, from Newcastle and Sussex universities, also reported that surviving brain cells in the brainstem have more copies of mitochondrial DNA and this has not been identified before.

The study’s insights into Parkinson’s disease suggests a new target for therapies for patients with the debilitating condition. The findings are surprising, since the results differ from what has been seen in studies of brain regions that harbor other brain cell-types.

“Our study is a major step forwards in gaining an enhanced insight into the serious condition. Only by understanding the complexities of what happens in specific cell-types found in specific areas of the brain during this disease can targeted treatments for Parkinson’s disease be produced,”

said Dr. Joanna Elson, a mitochondrial geneticist at Newcastle University.

Pedunculopontine Nucleus Changes

Research shows that in Parkinson’s disease, a brainstem region called the pedunculopontine nucleus (PPN) develops changes in DNA found in mitochondria — the batteries of the cell — as they produce and store energy that cells can use.

This study looked at cholinergic neurons that are responsible for producing the brain chemical acetylcholine, which is released by cholinergic nerve cells to send signals from one neuron to another.

Death of these cells in the PPN is believed to be the cause of some of the symptoms of Parkinson’s disease, such as problems with attention, walking and posture. Identifying changes in the mitochondrial DNA in PPN cholinergic neurons has the potential to allow the development of more effective treatments targeted to specific cell-types.

The PPN is an understudied part of the brain. Researchers used post-mortem tissue from the Newcastle Brain Tissue Resource, based at Newcastle University, to isolate single neurons for in-depth analysis.

Targeted Parkinson’s Disease Treatment

Parkinson’s disease is a condition in which part of the brain becomes progressively damaged over many years. It is estimated that around one in 500 people in the UK are affected by the condition.

Dr. Ilse Pienaar, a neuroscientist at Sussex University, said:

“At present, treatments are aimed at the whole brain of patient’s with Parkinson’s disease. Only by understanding the complexities of what happens in specific cell-types found in specific areas of the brain during this disease can targeted treatments be produced. We believe that not only would cell-specific targeted treatments be more effective, but they would also be associated with fewer side-effects.”

The PPN was of interest because, in previous studies, patients with Parkinson’s disease displayed lower levels of mitochondrial DNA (mtDNA) in remaining dopaminergic neurons.

This study showed that mtDNA levels are higher in the surviving cholinergic neurons of the brainstem, but with both cell-types that undergo profound degeneration during Parkinson’s disease. The finding identifies how vulnerable cell groups react and respond differently to the accumulation of mitochondrial DNA damage seen in the disease, highlighting the need for cell-specific treatments.

The researchers are now aiming to continue with further research to investigate the findings and test the mechanisms by which targeted treatment could be delivered to patients.

Bury, A. G., Pyle, A., Elson, J. L., Greaves, L., Morris, C. M., Hudson, G. and Pienaar, I. S.
Mitochondrial DNA changes in pedunculopontine cholinergic neurons in Parkinson disease
Ann Neurol., 82: 1016–1021. doi:10.1002/ana.25099

Image: Georgia Drysdale. Wellcome Images