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

Lookup NU author(s): Dr Ilse Pienaar, Dr Joanna Elson, Dr Claudia Racca, Dr Glyn NelsonORCiD, Emeritus Professor Doug Turnbull, Dr Christopher Morris

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Abstract

Cholinergic neuronal loss in the pedunculopontine nucleus (PPN) associates with abnormal functions, including certain motor and non-motor symptoms. This realization has led to low-frequency stimulation of the PPN for treating Parkinson’s disease (PD) patients 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 towards designing more efficient therapies aimed at restoring the PPN’s normal functions during progressive Parkinsonism. Here we investigated post-mortem pathological changes in the PPN of PD cases. Our study detected a loss of GABAergic and glycinergic neurons, with an even more pronounced loss of cholinergic neurons, accompanied by altered somatic cell size affecting the remaining neurons of all neuronal subtypes studied here. Since 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 upregulation of several mitochondrial proteins was seen in GABAergic and glycinergic neurons; however, cholinergic neurons revealed downregulation of the same proteins. Our findings suggest an imbalance in the activity of key neuronal subgroups of the PPN in PD, potentially due to abnormal inhibitory activity and altered cholinergic outflow.


Publication metadata

Author(s): Pienaar I-S, Elson JL, Racca C, Nelson G, Turnbull DM, Morris CM

Publication type: Article

Publication status: Published

Journal: American Journal of Pathology

Year: 2013

Volume: 183

Issue: 6

Pages: 1826-1840

Print publication date: 04/10/2013

ISSN (print): 0002-9440

ISSN (electronic): 1525-2191

Publisher: Elsevier

URL: http://dx.doi.org/10.1016/j.ajpath.2013.09.002

DOI: 10.1016/j.ajpath.2013.09.002


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Funding

Funder referenceFunder name
G0700718UK's Medical Research Council (MRC), cross council Lifelong Health and Wellbeing Initiative
Alzheimer's Association through an NIHR Biomedical Research Centre Grant in Ageing and Health
Engineering and Physical Sciences Research Council (EPSRC)
Rosetrees Trust
UK Department of Health
UK's National Institute for Health Research (NIHR) Biomedical Research Centre for Ageing and Age-related disease award
Alzheimer's Association through the Brains for Dementia Research Initiative
Alzheimer's Research Trust
Biotechnology and Biological Sciences Research Council (BBSRC)
Economic and Social Research Council (ESRC)
Faculty Fellowship from the Imperial College London
Newcastle University Centre for Brain Ageing and Vitality
Research Council UK (RCUK)
UK MRC
906919Wellcome Trust Centre for Mitochondrial Research

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