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BAG1 is Neuroprotective in In Vivo and In Vitro Models of Parkinson’s Disease

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Abstract

Bcl-2-associated athanogene-1 (BAG1) is a multifunctional protein comprising co-chaperone function, increasing Hsp70 foldase activity and chaperone-dependent protein degradation of misfolded substrates, with anti-apoptotic activity. It is neuroprotective in different models of neurological diseases, like cerebral ischemia and Huntington’s disease. In the context of Parkinson’s disease, it has recently been shown to restore DJ-1 function in an in vitro model of hereditary Parkinson’s disease. Here, we demonstrate that BAG1 overexpression in SH-SY5Y cells reduces toxicity after transfection of disease-related α-synuclein mutants. Furthermore, it protects from rotenone-induced cell death in vitro and ameliorates neuronal demise in an in vivo 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) model for Parkinson’s disease after adeno-associated virus (AAV)-mediated BAG1 gene transfer into the substantia nigra in mice but showed no protective effects in an in vitro 6-hydroxidopamine model. In conclusion, we present BAG1 as a potential therapeutic target in Parkinson’s disease.

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Funding Source

The work was supported by the DFG Research Center for Molecular Physiology of the Brain (CMPB), Göttingen, Germany, the NeuroNE network of excellence within the 6th framework program of the European Union, and Starter Grants of the University Medical Center Goettingen.

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Authors and Affiliations

  1. Department of Neurology, Nordwest-Krankenhaus Sanderbusch, Sande, Germany

    Pawel Kermer

  2. Department of Neuropediatrics, University Medical Center Göttingen, Göttingen, Germany

    Anja Köhn

  3. Department of Neurology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany

    Marlena Schnieder, Paul Lingor, Mathias Bähr, Jan Liman & Christoph Peter Dohm

  4. DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany

    Pawel Kermer, Anja Köhn, Marlena Schnieder, Paul Lingor, Mathias Bähr, Jan Liman & Christoph Peter Dohm

Authors
  1. Pawel Kermer
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  2. Anja Köhn
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  3. Marlena Schnieder
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  4. Paul Lingor
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  5. Mathias Bähr
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  6. Jan Liman
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  7. Christoph Peter Dohm
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Corresponding author

Correspondence to Jan Liman.

Additional information

Pawel Kermer and Anja Köhn contributed equally.

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Supplementary Fig. S1

Stable expression in SH-SY5Y cells was shown via western blotting using a BAG1 antibody. Expression of BAG1 can only be seen in cells stably overexpressing BAG1, but not in the empty vector transfected cells. β-Tubulin staining served as protein loading control. (JPEG 7 kb)

Supplementary Fig. S2

Expression of the different α-Synuclein constructs on protein level was tested via western blotting against α-Synuclein. The expression levels of the different mutants are comparable. β-Tubulin staining served as protein loading control. (JPEG 26 kb)

Supplementary Fig. S3

Expression of the BAG1 protein after viral transduction of the SN was tested via immunohistochemistry with a) staining against BAG1 b) viral EGFP expression. As shown in the merged picture EGFP and BAG1 are co localising (c). (scale bar = 50 μm) (JPEG 26 kb)

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Kermer, P., Köhn, A., Schnieder, M. et al. BAG1 is Neuroprotective in In Vivo and In Vitro Models of Parkinson’s Disease. J Mol Neurosci 55, 587–595 (2015). https://doi.org/10.1007/s12031-014-0396-2

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  • DOI: https://doi.org/10.1007/s12031-014-0396-2

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