Mitochondrial Abnormality Associates with Type-Specific Neuronal Loss and Cell Morphology Changes in the Pedunculopontine Nucleus in Parkinson Disease

Abstract

Cholinergic neuronal loss in the pedunculopontine nucleus (PPN) associates with abnormal functions, including certain motor and nonmotor symptoms. This realization has led to low-frequency stimulation of the PPN for treating patients with Parkinson disease (PD) who are refractory to other treatment modalities. However, the molecular mechanisms underlying PPN neuronal loss and the therapeutic substrate for the clinical benefits following PPN stimulation remain poorly characterized, hampering progress toward designing more efficient therapies aimed at restoring the PPN's normal functions during progressive parkinsonism. Here, we investigated postmortem pathological changes in the PPN of PD cases. Our study detected a loss of neurons producing gamma-aminobutyric acid (GABA) as their output and glycinergic neurons, along with the pronounced loss of cholinergic neurons. These losses were accompanied by altered somatic cell size that affected the remaining neurons of all neuronal subtypes studied here. Because studies showed that mitochondrial dysfunction exists in sporadic PD and in PD animal models, we investigated whether altered mitochondrial composition exists in the PPN. A significant up-regulation of several mitochondrial proteins was seen in GABAergic and glycinergic neurons; however, cholinergic neurons indicated down-regulation of the same proteins. Our findings suggest an imbalance in the activity of key neuronal subgroups of the PPN in PD, potentially because of abnormal inhibitory activity and altered cholinergic outflow.

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

“…During later phases of the disease, other signs and symptoms emerge, specifically gait and balance problems, and cognitive impairments. It is widely believed that balance problems are the result of degeneration in the portion of the PPN that belongs to the mesencephalic locomotor region and/or degeneration of cholinergic cell groups [e.g., 90,[133][134][135][136][137][138][139]. Cognitive impairments are likely caused by a combination of factors, including the extension of significant dopamine loss to nonmotor portions of the basal ganglia, and the spread of pathology to prefrontal cortical regions [132].…”

“…This constellation of findings suggests the possibility that the descending basal ganglia projections to the brainstem may play a greater role in the pathophysiology of akinesia/bradykinesia and movement than is commonly assumed. A particular role of the PPN in the axial control of gait and balance, and in abnormalities of these functions in patients with movement disorders, is suggested by the fact that portions of the PPN are part of the brainstem locomotor region [90,137,138], and the finding that PPN neurons in this region degenerate in PD [133][134][135][136].…”

Mitochondrial DNA changes in pedunculopontine cholinergic neurons in Parkinson disease

“…Cholinergic neuronal loss co-occurs, particularly within a brainstem structure, the pedunculopontine nucleus (PPN). [2][3][4] Surviving (but susceptible) cholinergic neurons in these nuclei contain aggregated a-synuclein fibrils, forming Lewy bodies and Lewy neurites, a neuropathological hallmark of PD. Mitochondrial DNA (mtDNA) copy number and mtDNA deletions were increased significantly in PD patients compared to controls.…”

Continuous stimulation of the pedunculopontine tegmental nucleus at 40Hz affects preparative and executive control in a delayed sensorimotor task and reduces rotational movements induced by apomorphine in the 6-OHDA parkinsonian rat

“…It is still unknown to what extent each of these neuronal populations is specifically involved in the above-mentioned motor and non-motor functions. It is also worth noting that recent data indicate that in PD patients, a loss of cholinergic as well as non-cholinergic neurons occurs in the PPTg [30].…”