title: An animal model mimicking pedunculopontine nucleus cholinergic degeneration in Parkinson's disease.
abstract: 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.
authors.affiliation: Division of Brain Sciences, Department of Medicine, Centre for Neuroinflammation and Neurodegeneration, Imperial College London, London, W12 ONN, UK, i.pienaar@imperial.ac.uk.
authors.forename: Ilse S
authors.initials: IS
authors.lastname: Pienaar
authors.forename: Ian F
authors.initials: IF
authors.lastname: Harrison
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Elson
authors.forename: Alexander
authors.initials: A
authors.lastname: Bury
authors.forename: Petter
authors.initials: P
authors.lastname: Woll
authors.forename: Anna Katharina
authors.initials: AK
authors.lastname: Simon
authors.forename: David T
authors.initials: DT
authors.lastname: Dexter
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002452:Cell Count; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D059329:Cholinergic Neurons / Q000473:pathology*; D015853:Cysteine Proteinase Inhibitors / Q000633:toxicity; D004195:Disease Models, Animal; D005552:Forelimb / Q000503:physiopathology; D007839:Functional Laterality; D007091:Image Processing, Computer-Assisted; D061346:Laser Capture Microdissection; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009043:Motor Activity; D009124:Muscle Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000209:etiology*; D010300:Parkinson Disease / Q000150:complications* / Q000209:etiology; D045042:Pedunculopontine Tegmental Nucleus / Q000473:pathology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D002135:Calcium-Binding Proteins; D015853:Cysteine Proteinase Inhibitors; D008565:Membrane Proteins; D009124:Muscle Proteins; C116337:OX-6 monoclonal antibody; C091825:syntrophin alpha1; C067713:lactacystin; D014446:Tyrosine 3-Monooxygenase; D002795:Choline O-Acetyltransferase; D010751:Phosphopyruvate Hydratase; D000111:Acetylcysteine