TY - JOUR
T1 - Olfactory neuron-specific expression of A30P alpha-synuclein exacerbates dopamine deficiency and hyperactivity in a novel conditional model of early Parkinson's disease stages
AU - Nuber, Silke
AU - Petrasch-Parwez, Elisabeth
AU - Arias-Carrión, Oscar
AU - Koch, Leanie
AU - Kohl, Zacharias
AU - Schneider, Jacqueline
AU - Calaminus, Carsten
AU - Dermietzel, Rolf
AU - Samarina, Anna
AU - Boy, Jana
AU - Nguyen, Huu P.
AU - Teismann, Peter
AU - Velavan, Thirumalaisamy Palanichamy
AU - Kahle, Philipp J.
AU - von Hörsten, Stephan
AU - Fendt, Markus
AU - Krüger, Rejko
AU - Riess, Olaf
N1 - Funding Information:
This work was supported by a German Research Foundation Grant DFG ( RI 682/6-1/3 ) to O.R., the Federal Ministry for Education and Research (BMBF, NGFNplus; 01GS08134 to O.R. and R.K, the Bavarian State Ministry of Sciences, Research and the Arts , ForNeuroCell to J.W; Erlangen, Germany; and the Elite Network Bavaria to J.W. S.N. is a fellow of the German Parkinson's Disease Society. We thank our colleagues for fruitful discussion in particular J. Winkler, G. Höglinger and T. Schmidt. We thank H.-W. Habbes, and M. Löbbecke-Schumacher for excellent technical assistance and C. Soehnrey, T. Endres, C.Wurst and N. Kurka for help in behavioral studies. We thank B. Pichler and K. Fischer for microPET analysis and Stanley B. Prusiner for supplying PrP-tTA transgenic mice.
PY - 2011/11
Y1 - 2011/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80052287774&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2011.06.017
DO - 10.1016/j.nbd.2011.06.017
M3 - Article
C2 - 21767644
AN - SCOPUS:80052287774
SN - 0969-9961
VL - 44
SP - 192
EP - 204
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 2
ER -