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FASEB J. 2019 Feb;33(2):2116-2131. doi: 10.1096/fj.201800148RRR. Epub 2018 Sep 25.

Monitoring α-synuclein multimerization in vivo.

Author information

1
Department of Neurology, University Medical Center, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany.
2
Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, German Center for Neurodegenerative Diseases, Tübingen, Germany.
3
Institute of Neuropathology, University Medical Center, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany.
4
Department of Experimental Neurodegeneration, Center of Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany.
5
Max Planck Institute for Experimental Medicine, Göttingen, Germany.
6
Institute of Neuroscience, The Medical School, Newcastle University, Newcastle Upon Tyne, United Kingdom; and.
7
Jülich-Aachen Research Alliance (JARA)-Brain Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany.

Abstract

The pathophysiology of Parkinson's disease is characterized by the abnormal accumulation of α-synuclein (α-Syn), eventually resulting in the formation of Lewy bodies and neurites in surviving neurons in the brain. Although α-Syn aggregation has been extensively studied in vitro, there is limited in vivo knowledge on α-Syn aggregation. Here, we used the powerful genetics of Drosophila melanogaster and developed an in vivo assay to monitor α-Syn accumulation by using a bimolecular fluorescence complementation assay. We found that both genetic and pharmacologic manipulations affected α-Syn accumulation. Interestingly, we also found that alterations in the cellular protein degradation mechanisms strongly influenced α-Syn accumulation. Administration of compounds identified as risk factors for Parkinson's disease, such as rotenone or heavy metal ions, had only mild or even no impact on α-Syn accumulation in vivo. Finally, we show that increasing phosphorylation of α-Syn at serine 129 enhances the accumulation and toxicity of α-Syn. Altogether, our study establishes a novel model to study α-Syn accumulation and illustrates the complexity of manipulating proteostasis in vivo.-Prasad, V., Wasser, Y., Hans, F., Goswami, A., Katona, I., Outeiro, T. F., Kahle, P. J., Schulz, J. B., Voigt, A. Monitoring α-synuclein multimerization in vivo.

KEYWORDS:

BiFC; Parkinson’s disease; protein aggregation; synucleinopathy

PMID:
30252534
DOI:
10.1096/fj.201800148RRR

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