title: Orchestrated increase of dopamine and PARK mRNAs but not miR-133b in dopamine neurons in Parkinson's disease.
abstract: Progressive loss of substantia nigra dopamine neurons (SN DA) is a hallmark of aging and of Parkinson's disease (PD). Mutations in PARK genes cause familial PD forms. Increased expression of alpha-synuclein (PARK4) is a disease-triggering event in familial PD and also observed in SN DA neurons in sporadic PD but related transcriptional changes are unknown. With optimized single-cell quantitative real-time polymerase chain reaction analysis, we compared messenger RNA and microRNA levels in SN DA neurons from sporadic PD patients and controls. Non-optimally matched donor ages and RNA integrities are common problems when analyzing human samples. We dissected the influence of distinct ages and RNA integrities of our samples by applying a specifically-optimized, linear-mixed-effects model to quantitative real-time polymerase chain reaction-data. We identified that elevated alpha-synuclein messenger RNA levels in SN DA neurons of human PD brains were positively correlated with corresponding elevated levels of mRNAs for functional compensation of progressive SN DA loss and for enhanced proteasomal (PARK5/UCHL1) and lysosomal (PARK9/ATPase13A2) function, possibly counteracting alpha-synuclein toxicity. In contrast, microRNA miR-133b levels, previously implicated in transcriptional dysregulation in PD, were not altered in SN DA neurons in PD.
authors.affiliation: Department of Applied Physiology, Institute of Applied Physiology, University of Ulm, Ulm, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Schlaudraff
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Jan
authors.initials: J
authors.lastname: Gründemann
authors.affiliation: Department of Applied Physiology, Institute of Applied Physiology, University of Ulm, Ulm, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Fauler
authors.affiliation: Department of Applied Physiology, Institute of Applied Physiology, University of Ulm, Ulm, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Dragicevic
authors.affiliation: Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Department of Applied Physiology, Institute of Applied Physiology, University of Ulm, Ulm, Germany. Electronic address: birgit.liss@uni-ulm.de.
authors.forename: Birgit
authors.initials: B
authors.lastname: Liss
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D020961:Lewy Body Disease / Q000235:genetics*; D008247:Lysosomes / Q000502:physiology; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism*; D013378:Substantia Nigra / Q000166:cytology; D051844:alpha-Synuclein / Q000172:deficiency* / Q000235:genetics
chemical_list: C548234:MIRN133 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D051844:alpha-Synuclein; D046988:Proteasome Endopeptidase Complex; D004298:Dopamine
keywords: ATPase13A2; LRRK2; Mixed-effects-model; NURR1; PARK; PITX3; Parkin; RIN; SNCA140; UCHL-1; UV-LMD; miR-133b
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