Article (Scientific journals)
Olfactory neuron-specific expression of A30P alpha-synuclein exacerbates dopamine deficiency and hyperactivity in a novel conditional model of early Parkinson's disease stages.
Nuber, Silke; Petrasch-Parwez, Elisabeth; Arias-Carrion, Oscar et al.
2011In Neurobiology of Disease, 44 (2), p. 192-204
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Keywords :
Amino Acid Substitution/genetics; Animals; Cricetinae; Disease Models, Animal; Dopamine/biosynthesis/deficiency; Female; Humans; Hyperkinesis/genetics/metabolism/physiopathology; Male; Mice; Mice, Transgenic; Mutation/genetics; Neurons/metabolism/pathology; Olfactory Bulb/metabolism/pathology/physiopathology; Parkinsonian Disorders/genetics/metabolism/physiopathology; alpha-Synuclein/biosynthesis/genetics/physiology
Abstract :
[en] Mutations in the N-terminus of the gene encoding alpha-synuclein (alpha-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 alpha-syn, we evaluated effect and reversibility of olfactory synucleinopathy. Our data showed that induction of mutant A30P alpha-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 alpha-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) alpha-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.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group)
Disciplines :
Genetics & genetic processes
Author, co-author :
Nuber, Silke
Petrasch-Parwez, Elisabeth
Arias-Carrion, Oscar
Koch, Leanie
Kohl, Zacharias
Schneider, Jacqueline
Calaminus, Carsten
Dermietzel, Rolf
Samarina, Anna
Boy, Jana
Nguyen, Huu P.
Teismann, Peter
Velavan, Thirumalaisamy Palanichamy
Kahle, Philipp J.
von Horsten, Stephan
Fendt, Markus
KRÜGER, Rejko ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Riess, Olaf
More authors (8 more) Less
Language :
English
Title :
Olfactory neuron-specific expression of A30P alpha-synuclein exacerbates dopamine deficiency and hyperactivity in a novel conditional model of early Parkinson's disease stages.
Publication date :
2011
Journal title :
Neurobiology of Disease
ISSN :
1095-953X
Publisher :
Elsevier, Atlanta, United States - California
Volume :
44
Issue :
2
Pages :
192-204
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright (c) 2011 Elsevier Inc. All rights reserved.
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