Summary: A new study finds that in Parkinson’s disease, surviving neurons in a brainstem region called the pedunculopontine nucleus (PPN) contain higher numbers of mitochondrial DNA copies and more mitochondrial DNA damage, a discovery that helps explain cell loss in this area and points to new cell-specific therapy targets.
Source: Newcastle University
Researchers at Newcastle and Sussex universities report a previously unrecognized mitochondrial DNA change in brainstem neurons that may play a role in Parkinson’s disease.
A study published in the journal Annals of Neurology describes surprising differences in mitochondrial DNA (mtDNA) within specific neuron types in the brainstem compared with other brain regions affected by Parkinson’s disease. The findings provide fresh insight into cell-specific vulnerability and suggest new avenues for therapies that target particular cells rather than the entire brain.
Dr Joanna Elson, a mitochondrial geneticist at Newcastle University, said the work marks a major step forward in understanding the complex biology of Parkinson’s disease. She emphasized that treatments designed to address molecular changes in particular cell types and brain regions are essential to develop more effective and better-tolerated therapies.
Changes in cell DNA
The research focused on the pedunculopontine nucleus (PPN), a brainstem structure that contains cholinergic neurons—cells that produce the neurotransmitter acetylcholine. Cholinergic neurons in the PPN play important roles in attention, posture, and gait, and their loss is linked to some of the non-motor and motor symptoms experienced by people with Parkinson’s disease.
Using post-mortem tissue from the Newcastle Brain Tissue Resource, the team isolated single cholinergic neurons from the PPN of Parkinson’s patients and age-matched controls for detailed analysis. They measured mitochondrial DNA copy number and the presence of mtDNA deletions within individual cells.
Contrary to prior observations in other brain regions—where researchers had seen mtDNA depletion in dying dopaminergic neurons—the surviving cholinergic neurons in the PPN of Parkinson’s patients had elevated mtDNA copy numbers. At the same time, these neurons showed significantly higher levels of mtDNA deletions. Many PPN cholinergic neurons in patients carried deletion levels exceeding 60%, a threshold that can severely impair oxidative phosphorylation and mitochondrial function.
Dr Ilse Pienaar, a neuroscientist at Sussex University, noted that current Parkinson’s treatments typically act on the whole brain. By contrast, a cell-specific understanding of how mitochondrial damage accumulates in distinct neuron types could enable targeted therapies that are both more effective and produce fewer side effects.
The study’s results highlight how different neuronal populations respond differently to the accumulation of mitochondrial DNA damage. Where dopaminergic neurons in the substantia nigra show mtDNA depletion, cholinergic neurons in the PPN appear to survive with more mtDNA copies but with an increased burden of deletions. This contrast underscores the need to consider both the type of neuron and its regional environment when designing disease models and treatments.
Parkinson’s disease
Parkinson’s disease is a progressive neurological disorder in which specific brain regions and neuronal populations degenerate over many years. Symptoms can include tremor, slowness of movement, rigidity, balance and gait problems, as well as a range of non-motor symptoms such as cognitive impairment, sleep disturbances, and attention deficits. In the UK it is estimated that roughly one in 500 people are affected; globally, prevalence increases with age.
Dr Elson emphasized that this study is the first to characterize mitochondrial DNA alterations specifically in cholinergic neurons from the human PPN. By linking mtDNA changes to neuronal vulnerability in this cell population, the research contributes to a clearer picture of how mitochondrial dysfunction may drive both motor and non-motor features of Parkinson’s disease.
The authors plan to extend this work by investigating the mechanisms that lead to increased mtDNA copy number and deletions in PPN cholinergic neurons, and by testing approaches to deliver targeted treatments to these vulnerable cells.
About the research
Study title: “Mitochondrial DNA changes in pedunculopontine cholinergic neurons in Parkinson’s.” Authors include Alexander G. Bury, Angela Pyle, Joanna L. Elson, Laura Greaves, Christopher M. Morris, Gavin Hudson, and Ilse S. Pienaar. Published online December 4, 2017 in Annals of Neurology. The research examined single-cell mtDNA copy number and deletion levels in post-mortem PPN cholinergic neurons from Parkinson’s disease patients and controls, revealing increased mtDNA copy number and deletion burden in PD.
The findings point to the potential for developing cell-specific strategies that address mitochondrial dysfunction in selected neuronal populations—an approach that may yield more precise therapies with fewer systemic side effects than current treatments aimed at the whole brain.