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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.

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Abbreviations

ACh:

Acetylcholine

AOI:

Area of interest

asf:

Area sampling fraction

αSYN:

α-synuclein

ATG:

Autophagy-specific gene

ABC:

Avidin–biotin peroxidise complex

CNS:

Central nervous system

ChAT:

Choline acetyl transferase

CE:

Coefficient of error

CFV:

Cresyl fast violet

DBS:

Deep-brain stimulation

i.p:

Intraperitoneally

DAB:

3,3′-Diaminobenzidine

EtOH:

Ethanol

hsf:

Height sampling fraction

LCM:

Laser-capture microdissection

LDTg:

Laterodorsal tegmental nucleus

MR:

Magnetic resonance

MRI:

Magnetic resonance imaging

MHC:

Major histocompatibility complex

MFB:

Medial forebrain bundle

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MEMS:

Multi-echo multi-slice spin-echo pulse sequence

NeuN:

Neuronal-specific nuclear

NADPH:

Nicotinamide adenine dinucleotide phosphate

NGS:

Normal goat serum

NHS:

Normal horse serum

PD:

Parkinson’s disease

PBS:

Phosphate buffer saline

PBST:

Phosphate buffer solution with 0.1 % Triton X-100

PPN:

Pedunculopontine nucleus

PTFE:

Polytetrafluroethylane

PSP:

Progressive supranuclear palsy

REM:

Rapid eye movement sleep

ROS:

Reactive oxygen species

ROI:

Region of interest

RT:

Room temperature

6-OHDA:

6-Hydroxydopamine

ssf:

Section sampling fraction

SNpc:

Substantia nigra pars compacta

SNr:

Substantia Nigra pars reticulata

TE:

Tris-EDTA

T2W:

T2-weighted

TH:

Tyrosine hydroxylase

UCH-L1:

Ubiquitin C-terminal hydrolase L1

UPS:

Ubiquitin–proteasome system

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Acknowledgments

ISP holds an Imperial College London Jnr. Research Fellowship. This study received grant support from the Rosetrees Trust, awarded to ISP. IFH is supported by a UK Medical Research Council (MRC) Ph.D. studentship. AKS is supported by the National Institute for Health Research (NIHR) and the Oxford Biomedical Research Centre. All the authors commented on the paper and agreed on the final version of the manuscript.

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Correspondence to Ilse S. Pienaar.

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Pienaar, I.S., Harrison, I.F., Elson, J.L. et al. An animal model mimicking pedunculopontine nucleus cholinergic degeneration in Parkinson’s disease. Brain Struct Funct 220, 479–500 (2015). https://doi.org/10.1007/s00429-013-0669-5

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Keywords

  • Neurodegeneration
  • Cholinergic neurons
  • Parkinson’s disease
  • Pedunculopontine nucleus
  • Proteasomal inhibitor