Impaired Wnt signaling in dopamine containing neurons is associated with pathogenesis in a rotenone triggered Drosophila Parkinson's disease model

TY - JOUR

T1 - Impaired Wnt signaling in dopamine containing neurons is associated with pathogenesis in a rotenone triggered Drosophila Parkinson's disease model

AU - Stephano, Flora

AU - Nolte, Stella

AU - Hoffmann, Julia

AU - El-Kholy, Samar

AU - Von Frieling, Jakob

AU - Bruchhaus, Iris

AU - Fink, Christine

AU - Roeder, Thomas

PY - 2018/2/5

Y1 - 2018/2/5

N2 - Parkinson's disease, which is the one of the most common neurodegenerative movement disorder, is characterized by a progressive loss of dopamine containing neurons. The mechanisms underlying disease initiation and development are not well understood and causative therapies are currently not available. To elucidate the molecular processes during early stages of Parkinson's disease, we utilized a Drosophila model. To induce Parkinson's disease-like phenotypes, we treated flies with the pesticide rotenone and isolated dopamine producing neurons of animals that were at an early disease stage. Transcriptomic analyses revealed that gene ontologies associated with regulation of cell death and neuronal functions were significantly enriched. Moreover, the activities of the MAPK/EGFR- and TGF-β signaling pathways were enhanced, while the Wnt pathway was dampened. In order to evaluate the role of Wnt signaling for survival of dopaminergic neurons in the disease model, we rescued the reduced Wnt signaling activity by ectopic overexpression of armadillo/β-catenin. This intervention rescued the rotenone induced movement impairments in the Drosophila model. Taken together, this initial study showed a highly relevant role of Wnt signaling for dopamine producing neurons during pathogenesis in Parkinson's disease and it implies that interfering with this pathway might by a suitable therapeutic option for the future.

AB - Parkinson's disease, which is the one of the most common neurodegenerative movement disorder, is characterized by a progressive loss of dopamine containing neurons. The mechanisms underlying disease initiation and development are not well understood and causative therapies are currently not available. To elucidate the molecular processes during early stages of Parkinson's disease, we utilized a Drosophila model. To induce Parkinson's disease-like phenotypes, we treated flies with the pesticide rotenone and isolated dopamine producing neurons of animals that were at an early disease stage. Transcriptomic analyses revealed that gene ontologies associated with regulation of cell death and neuronal functions were significantly enriched. Moreover, the activities of the MAPK/EGFR- and TGF-β signaling pathways were enhanced, while the Wnt pathway was dampened. In order to evaluate the role of Wnt signaling for survival of dopaminergic neurons in the disease model, we rescued the reduced Wnt signaling activity by ectopic overexpression of armadillo/β-catenin. This intervention rescued the rotenone induced movement impairments in the Drosophila model. Taken together, this initial study showed a highly relevant role of Wnt signaling for dopamine producing neurons during pathogenesis in Parkinson's disease and it implies that interfering with this pathway might by a suitable therapeutic option for the future.

UR - http://www.scopus.com/inward/record.url?scp=85041672283&partnerID=8YFLogxK

U2 - 10.1038/s41598-018-20836-w

DO - 10.1038/s41598-018-20836-w

M3 - Journal article

C2 - 29403026

AN - SCOPUS:85041672283

SN - 2045-2322

VL - 8

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 2372

ER -