Cited by 145Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

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

Gallardo, Gilbert, Schlüter, Oliver M, Südhof, Thomas C·2008·Nature Neuroscience

Abstract

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

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Crossref · 10.1038/nn2058

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  • Genetic ablation of ApoE in various neurodegenerative mouse models shows a similar protective effect against neurodegeneration and disease severity.

    “Notably, genetic ablation of ApoE in various neurodegenerative mouse models — including tauopathy69, synucleinopathy106, and experimental autoimmune encephalomyelitis (EAE)107 — shows a similar protective effect against neurodegeneration and disease severity”
  • In a mouse model of Parkinson's disease featuring synucleinopathy, ApoE deletion significantly attenuates loss of spinal cord motor neurons, delays disease onset, and improves survival.

    “In a mouse model of Parkinson’s disease featuring synucleinopathy, ApoE deletion significantly attenuates the loss of spinal cord motor neurons, delays disease onset, and improves survival106.”

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Authors
Gallardo, G., Schlüter, O. M., & Südhof, T. C.
Affiliations
  • The University of Texas Southwestern Medical Center (US)
  • European Neuroscience Institute Göttingen (DE)
  • Howard Hughes Medical Institute (US)
Corresponding author
Gallardo, Gilbert
Venue
Nature Neuroscience
Published
2008-02-24
Volume
11
Issue
3
Pages
301-308
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
OpenAlex
W1564677510
Cited by
145
References
48
Citations by year
2026: 2 · 2025: 7 · 2024: 8 · 2023: 6 · 2022: 8 · 2021: 6 · 2020: 5 · 2019: 10 · 2018: 9 · 2017: 8 · 2016: 5 · 2015: 6 · 2014: 3 · 2013: 9 · 2012: 13
FWCI
8.50
Type
journal article
Language
en
Open access
closed
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health
  • National Institute of Mental Health (R01MH069585)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
alpha-synuclein, apolipoprotein E, amyloid-beta, Parkinson's disease, Alzheimer's disease, neurodegeneration, ubiquitin-proteasome system, transgenic mice, protein aggregation, extracellular signaling
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Brain, Humans, Mice, Transgenic, Nerve Degeneration, Parkinson Disease, Peptides, Signal Transduction, Amyloid beta-Peptides, Cell Death, Mice, Knockout, Neurodegenerative Diseases, Lewy Body Disease, Ubiquitin, Proteasome Endopeptidase Complex, Mice, alpha-Synuclein

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