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Predominant Neuritic Pathology Induced by Viral Overexpression of α-Synuclein in Cell Culture

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1. Alpha-synuclein is known to play an important role in the pathogenesis of Parkinson’s disease (PD). The pathogenicity of α-synuclein is related to its ability to form intraneuronal inclusions. The inclusions, which are found in brains of patients with PD and diffuse Lewy body disease consist partially of C-terminally truncated α-synuclein. This α-synuclein species has an increased ability to form aggregates compared to full length α-synuclein.

2. We have used an adeno-associated virus (AAV) vector system to overexpress either C-terminally truncated or full length α-synuclein containing the A53T mutation, which have both been identified in brains of familial PD patients and transgenic mouse models. Dissociated mesencephalic neurons, cerebellar granule neurons, and organotypic midbrain slice cultures were infected with AAV containing the transgene under the control of the cytomegalovirus promoter.

3. We demonstrate that viral overexpression of α-synuclein(A53T) leads to the formation of distorted neurites, intraneuritic swellings, and granular perikaryal deposits in cultured neurons. Our results indicate that these cell culture models may represent an early phase of PD reflecting pathologic neuritic alterations before significant neuronal cell loss occurs.

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Abbreviations

AAV:

adeno-associated virus

AD:

Alzheimer’s disease

CGN:

cerebellar granule neuron

CMV:

cytomegalovirus

CSPα:

cystein-string-protein-α

DA:

dopaminergic

EGFP:

enhanced green fluorescent protein

HBSS:

Hank’s balanced salt solution

PD:

Parkinson’s disease

TUNEL:

terminal deoxyribonucleotidyl transferase (TdT)-mediated biotin-16-dUTP nick-end labeling

WT:

wild-type.

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Authors and Affiliations

  1. Boehringer Ingelheim Pharma GmbH & Co. KG, CNS Research, Birkendorferstrasse 65, 88397, Biberach an der Riss, Germany

    S. Zach, B. Hengerer & F. Gillardon

  2. Institute of Molecular Biology, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland

    H. Bueler

  3. Boehringer Ingelheim Pharma GmbH & Co. KG, CNS Research, Birkendorferstrasse 65, 88397, Biberach an der Riss, Germany

    S. Zach

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  1. S. Zach
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Correspondence to S. Zach.

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Zach, S., Bueler, H., Hengerer, B. et al. Predominant Neuritic Pathology Induced by Viral Overexpression of α-Synuclein in Cell Culture. Cell Mol Neurobiol 27, 505–515 (2007). https://doi.org/10.1007/s10571-007-9141-5

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