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A rostral brainstem structure, the pedunculopontine nucleus (PPN), is severely affected by Parkinson's disease (PD) pathology and is regarded a promising target for therapeutic deep-brain stimulation (DBS). However, understanding the PPN's role in PD and assessing the potential of DBS are hampered by the lack of a suitable model of PPN degeneration. Rats were rendered Parkinsonian through a unilateral substantia nigra pars compacta (SNpc) stereotaxic injection of the proteasome inhibitor Lactacystin, to investigate whether the lesion's pathological effects spread to impact the integrity of PPN cholinergic neurons which are affected in PD. At 5 weeks post-surgery, stereological analysis revealed that the lesion caused a 48 % loss of dopaminergic SNpc neurons and a 61 % loss of PPN cholinergic neurons, accompanied by substantial somatic hypotrophy in the remaining cholinergic neurons. Magnetic resonance imaging revealed T2 signal hyper-/hypointensity in the PPN of the injected hemisphere, respectively at weeks 3 and 5 post-lesion. Moreover, isolated PPN cholinergic neurons revealed no significant alterations in key autophagy mRNA levels, suggesting that autophagy-related mechanisms fail to protect the PPN against Lactacystin-induced cellular changes. Hence, the current results suggest that the Lactacystin PD model offers a suitable model for investigating the role of the PPN in PD.

Original publication

DOI

10.1007/s00429-013-0669-5

Type

Journal article

Journal

Brain structure & function

Publication Date

01/2015

Volume

220

Pages

479 - 500

Addresses

Division of Brain Sciences, Department of Medicine, Centre for Neuroinflammation and Neurodegeneration, Imperial College London, London, W12 ONN, UK, i.pienaar@imperial.ac.uk.

Keywords

Pedunculopontine Tegmental Nucleus, Forelimb, Animals, Rats, Rats, Sprague-Dawley, Parkinson Disease, Disease Models, Animal, Nerve Degeneration, Phosphopyruvate Hydratase, Tyrosine 3-Monooxygenase, Choline O-Acetyltransferase, Acetylcysteine, Calcium-Binding Proteins, Muscle Proteins, Membrane Proteins, Antibodies, Monoclonal, Cysteine Proteinase Inhibitors, Magnetic Resonance Imaging, Cell Count, Analysis of Variance, Motor Activity, Image Processing, Computer-Assisted, Male, Functional Laterality, Cholinergic Neurons, Laser Capture Microdissection