title: Dopamine-depletion and increased α-synuclein load induce degeneration of cortical cholinergic fibers in mice.
abstract: Cognitive dysfunction can be common among Parkinson's disease (PD) patients, and multiplication of the gene α-synuclein (αsyn) increases the risk of dementia. Here, we studied the role of dopamine-depletion and increased αsyn load and aggregation on cholinergic structures in vivo. Wild-type (WT) and mice with A30P αsyn overexpression were treated subacutely with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and the number of cholinergic cells in their nucleus basalis magnocellularis-substantia innominata (NBM-SI), their cortical fiber density and their expression of different genes 1day or 90 days after the last MPTP-injection were measured. Long-term dopamine depletion decreased the expression of choline acetyl transferase (ChAT) in the NBM-SI of WT mice, but no neuron loss was observed. In contrast, cortical cholinergic fiber density was decreased three months after MPTP-injection. Increased brain-derived neurotrophic factor expression could maintain cholinergic functions under these conditions. Expression of A30P αsyn in six-months-old transgenic mice resulted in decreased tyrosine receptor kinase B expression, and lower cortical cholinergic fiber density. Dopamine-depletion by MPTP induced cholinergic cell loss in the NBM-SI and increased cortical fiber loss. Our findings may explain why cholinergic cells are more vulnerable in PD, leading to an increased probability of dementia.
authors.affiliation: Department of NeuroDegeneration and Restorative Research, Georg-August University, DFG Research Center, Molecular Physiology of the Brain (CMPB), Göttingen, 37073, Germany. eszego@uni-goettingen.de
authors.forename: Éva M
authors.initials: ÉM
authors.lastname: Szego
authors.forename: Ellen
authors.initials: E
authors.lastname: Gerhardt
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Outeiro
authors.forename: Pawel
authors.initials: P
authors.lastname: Kermer
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism; D000409:Alanine / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002799:Cholinergic Fibers / Q000473:pathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000172:deficiency*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D020267:MPTP Poisoning / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000201:enzymology; D011392:Proline / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D020813:Receptor, trkB / Q000378:metabolism; D013997:Time Factors; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051844:alpha-Synuclein; D051028:bcl-2-Associated X Protein; C052617:Bcl2 protein, mouse; D011392:Proline; D002795:Choline O-Acetyltransferase; D020813:Receptor, trkB; D000110:Acetylcholinesterase; D000409:Alanine; D004298:Dopamine