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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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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DOI: https://doi.org/10.1007/s00429-013-0669-5