Article abstract
Nature Neuroscience 11, 301 - 308 (2008)
Published online: 24 February 2008 | doi:10.1038/nn2058
A molecular pathway of neurodegeneration linking 
-synuclein to ApoE and A
peptides
Gilbert Gallardo1, Oliver M Schlüter2,3 & Thomas C Südhof1,4,5
Abstract
Pathogenic aggregates of 
-synuclein are thought to contribute to the development of Parkinson's disease. Inclusion bodies containing -synuclein are present in Parkinson's disease and other neurodegenerative diseases, including Alzheimer's disease. Moreover, -synuclein mutations are found in cases of familial Parkinson's disease, and transgenic overexpression of -synuclein causes neurodegeneration in mice. The molecular mechanisms involved, however, remain incompletely understood. Here we show that, in transgenic mice, -synuclein induced neurodegeneration involves activation of the ubiquitin/proteasome system, a massive increase in apolipoprotein E (ApoE) levels and accumulation of insoluble mouse A
. ApoE was not protective, but was injurious, as deletion of ApoE delayed the neurodegeneration caused by -synuclein and suppressed the accumulation of A. Our data reveal a molecular link between central pathogenic mechanisms implicated in Parkinson's disease and Alzheimer's disease and suggest that intracellular -synuclein is pathogenic, at least in part, by activation of extracellular signaling pathways involving ApoE.
- Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-9111, USA.
- Department of Molecular Neurobiology, Max-Planck-Institut für experimentelle Medizin, 37075 Göttingen, Germany.
- European Neuroscience Institute, 37075 Göttingen, Germany.
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blud., Dallas, Texas 75390-9111, USA.
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Blud., Dallas, Texas 75390-9111, USA.
Correspondence to: Gilbert Gallardo1 e-mail: gilbert.gallardo@utsouthwestern.edu
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