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A molecular pathway of neurodegeneration linking α-synuclein to ApoE and Aβ peptides

Nature Neuroscience volume 11, pages 301–308 (2008)Cite this article

Abstract

Pathogenic aggregates of α-synuclein are thought to contribute to the development of Parkinson's disease. Inclusion bodies containing α-synuclein are present in Parkinson's disease and other neurodegenerative diseases, including Alzheimer's disease. Moreover, α-synuclein mutations are found in cases of familial Parkinson's disease, and transgenic overexpression of α-synuclein causes neurodegeneration in mice. The molecular mechanisms involved, however, remain incompletely understood. Here we show that, in transgenic mice, α-synuclein induced neurodegeneration involves activation of the ubiquitin/proteasome system, a massive increase in apolipoprotein E (ApoE) levels and accumulation of insoluble mouse Aβ. ApoE was not protective, but was injurious, as deletion of ApoE delayed the neurodegeneration caused by α-synuclein and suppressed the accumulation of Aβ. Our data reveal a molecular link between central pathogenic mechanisms implicated in Parkinson's disease and Alzheimer's disease and suggest that intracellular α-synuclein is pathogenic, at least in part, by activation of extracellular signaling pathways involving ApoE.

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Figure 1: Phenotype of mice expressing A30P-mutant α-synuclein.
Figure 2: Spinal cord neurodegeneration in α-synuclein transgenic mice involves the UPS.
Figure 3: Spinal cord neurodegeneration in α-synuclein transgenic mice involves increased ApoE.
Figure 4: Spinal cord neurodegeneration in α-synuclein transgenic mice involves increased levels of Aβ and cellular Aβ immunostaining.
Figure 5: Deletion of ApoE protects against α-synuclein–induced neurodegeneration.
Figure 6: Deletion of ApoE decreases ubiquitin and increases α-synuclein solubility in A30P-mutant α-synuclein transgenic mice.
Figure 7: Deletion of ApoE decreases formation of cellular Aβ immunostaining and Aβ levels in A30P-mutant α-synuclein transgenic mice.

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Acknowledgements

We would like to thank I. Kornblum, L. Fan, J. Mitchell and A. Roth for excellent technical assistance. This paper was supported by US National Institutes of Health Grant R01 MH069585 (to T.C.S.).

Author information

Authors and Affiliations

  1. Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, 75390-9111, Texas, USA

    Gilbert Gallardo & Thomas C Südhof

  2. Department of Molecular Neurobiology, Max-Planck-Institut für experimentelle Medizin, Göttingen, 37075, Germany

    Oliver M Schlüter

  3. European Neuroscience Institute, Göttingen, 37075, Germany

    Oliver M Schlüter

  4. Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blud., Dallas, 75390-9111, Texas, USA

    Thomas C Südhof

  5. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Blud., Dallas, 75390-9111, Texas, USA

    Thomas C Südhof

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  1. Gilbert Gallardo
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  3. Thomas C Südhof
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Contributions

G.G. conducted and analyzed the experiments and wrote the manuscript. O.M.S. contributed transgenic mice used for the study. T.C.S. designed the experiments, analyzed the data and wrote the manuscript.

Corresponding author

Correspondence to Gilbert Gallardo.

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Gallardo, G., Schlüter, O. & Südhof, T. A molecular pathway of neurodegeneration linking α-synuclein to ApoE and Aβ peptides. Nat Neurosci 11, 301–308 (2008). https://doi.org/10.1038/nn2058

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