title: Olfactory neuron-specific expression of A30P α-synuclein exacerbates dopamine deficiency and hyperactivity in a novel conditional model of early Parkinson's disease stages.
abstract: Mutations in the N-terminus of the gene encoding α-synuclein (α-syn) are linked to autosomal dominantly inherited Parkinson's disease (PD). The vast majority of PD patients develop neuropsychiatric symptoms preceding motor impairments. During this premotor stage, synucleinopathy is first detectable in the olfactory bulb (OB) and brain stem nuclei; however its impact on interconnected brain regions and related symptoms is still less far understood. Using a novel conditional transgenic mouse model, displaying region-specific expression of human mutant α-syn, we evaluated effect and reversibility of olfactory synucleinopathy. Our data showed that induction of mutant A30P α-syn expression increased transgenic deposition into somatodendritic compartment of dopaminergic neurons, without generating fibrillar inclusions. We found reversibly reduced levels of dopamine and metabolites in the OB, suggesting an impact of A30P α-syn on olfactory neurotransmitter content. We further showed that mutant A30P expression led to neurodegenerative changes on an ultrastructural level and a behaviorally hyperactive response correlated with novelty, odor processing and stress associated with an increased dopaminergic tone in midbrain regions. Our present data indicate that mutant (A30P) α-syn is directly implicated in reduction of dopamine signaling in OB interneurons, which mediates further alterations in brain regions without transgenic expression leading functionally to a hyperactive response. These modulations of neurotransmission may underlie in part some of the early neuropsychiatric symptoms in PD preceding dysfunction of the nigrostriatal dopaminergic system.
authors.affiliation: Department of Medical Genetics, University of Tuebingen, Germany. silke.nuber@med.uni-tuebingen.de
authors.forename: Silke
authors.initials: S
authors.lastname: Nuber
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Petrasch-Parwez
authors.forename: Oscar
authors.initials: O
authors.lastname: Arias-Carrión
authors.forename: Leanie
authors.initials: L
authors.lastname: Koch
authors.forename: Zacharias
authors.initials: Z
authors.lastname: Kohl
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Schneider
authors.forename: Carsten
authors.initials: C
authors.lastname: Calaminus
authors.forename: Rolf
authors.initials: R
authors.lastname: Dermietzel
authors.forename: Anna
authors.initials: A
authors.lastname: Samarina
authors.forename: Jana
authors.initials: J
authors.lastname: Boy
authors.forename: Huu P
authors.initials: HP
authors.lastname: Nguyen
authors.forename: Peter
authors.initials: P
authors.lastname: Teismann
authors.forename: Thirumalaisamy Palanichamy
authors.initials: TP
authors.lastname: Velavan
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Kahle
authors.forename: Stephan
authors.initials: S
authors.lastname: von Hörsten
authors.forename: Markus
authors.initials: M
authors.lastname: Fendt
authors.forename: Rejko
authors.initials: R
authors.lastname: Krüger
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D006224:Cricetinae; D004195:Disease Models, Animal; D004298:Dopamine / Q000096:biosynthesis / Q000172:deficiency*; D005260:Female; D006801:Humans; D006948:Hyperkinesis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009830:Olfactory Bulb / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D051844:alpha-Synuclein / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology
chemical_list: C497604:SNCA protein, human; D051844:alpha-Synuclein; D004298:Dopamine