title: Pedunculopontine cell loss and protein aggregation direct microglia activation in parkinsonian rats.
abstract: We previously reported a loss of cholinergic neurons within the pedunculopontine tegmental nucleus (PPTg) in rats that had been intra-nigrally lesioned with the proteasomal inhibitor lactacystin, with levels of neuronal loss corresponding to that seen in the post-mortem pedunculopontine nucleus (PPN) of advanced Parkinson's disease (PD) patients. Here we reveal lower expression values of the acetylcholine synthesising enzyme, choline acetyltransferase, within the remaining PPTg cholinergic neurons of lesioned rats compared to sham controls. We further characterise this animal model entailing dopaminergic- and non-dopaminergic neurodegeneration by reporting on stereological counts of non-cholinergic neurons, to determine whether the toxin is neuro-type specific. Cell counts between lesioned and sham-lesioned rats were analysed in terms of the topological distribution pattern across the rostro-caudal extent of the PPTg. The study also reports somatic hypotrophy in the remaining non-cholinergic neurons, particularly on the side closest to the nigral lesion. The cytotoxicity affecting the PPTg in this rat model of PD involves overexpression and accumulation of alpha-synuclein (αSYN), affecting cholinergic and non-cholinergic neurons as well as microglia on the lesioned hemispheric side. We ascertained that microglia within the PPTg become fully activated due to the extensive neuronal damage and neuronal death resulting from a lactacystin nigral lesion, displaying a distinct rostro-caudal distribution profile which correlates with PPTg neuronal loss, with the added implication that lactacystin-induced αSYN aggregation might trigger neuronophagia for promoting PPTg cell loss. The data provide critical insights into the mechanisms underlying the lactacystin rat model of PD, for studying the PPTg in health and when modelling neurodegenerative disease.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, UK.|Centre for Human Metabonomics, North-West University, Potchefstroom, South Africa.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Elson
authors.affiliation: School of Biomedical Sciences, Guy's Campus, King's College London, London, SE13QD, UK.
authors.forename: Abi
authors.initials: A
authors.lastname: Yates
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.|Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Ellison Place, Newcastle-upon-Tyne, NE1 8ST, UK. i.pienaar@imperial.ac.uk.
authors.forename: Ilse S
authors.initials: IS
authors.lastname: Pienaar
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives; D000818:Animals; D002452:Cell Count; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D059329:Cholinergic Neurons / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D008297:Male; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D065842:Pars Compacta / Q000378:metabolism / Q000473:pathology; D045042:Pedunculopontine Tegmental Nucleus / Q000378:metabolism* / Q000473:pathology*; D066263:Protein Aggregation, Pathological; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D051844:alpha-Synuclein; C067713:lactacystin; D014446:Tyrosine 3-Monooxygenase; D002795:Choline O-Acetyltransferase; D000111:Acetylcysteine
keywords: Lactacystin; Microglia; Neuronophagia; Parkinson’s disease; Pedunculopontine tegmental nucleus; α-Synuclein