. A molecular pathway of neurodegeneration linking alpha-synuclein to ApoE and Abeta peptides. Nat Neurosci. 2008 Mar;11(3):301-8. PubMed.


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  1. This paper by Sudhof and colleagues is quite interesting. The data are convincing that somehow, murine ApoE is involved in the spinal cord degeneration caused by overexpression of mutant α-synuclein in that the α-synuclein transgenic mice on an ApoE KO background have increased lifespan, decreased synuclein aggregation, decreased UPS activation, and decreased murine Aβ accumulation. It is not clear from genetic studies in humans whether ApoE isoforms influence risk or progression of Parkinson disease. However, this paper strongly suggests that somehow ApoE influences α-synuclein aggregation.

    Since ApoE is a secreted protein and most α-synuclein is believed to be cytoplasmic, whether ApoE and synuclein interact directly or indirectly is not yet clear. Synuclein can be found in the extracellular space such as in the CSF. Perhaps it is possible that ApoE and synuclein interact extracellularly. Alternatively, perhaps ApoE, being in lipoprotein particles in the brain, can in some way interact with synuclein after being internalized by cell surface receptors. Synuclein has lipoprotein-like properties and can interact with synaptic vesicle membranes and other intracellular membranes. Future studies may be able to address whether it can directly associate with ApoE via some of these membrane interactions. These findings open up a new area of investigation in relation to ApoE and synucleinopathy.

    View all comments by David Holtzman
  2. The recent work by Gallardo et al. made several novel and interesting findings that link ApoE and Aβ to α-synuclein-mediated neurodegeneration. Using a mouse model of Parkinson disease in which a mutant form of human α-synuclein is expressed, they show that mice with symptoms of neurodegeneration have increased levels of ApoE in the spinal cord and peripheral nerve compared to non-symptomatic mice. Additionally, the symptomatic mice have increased levels of endogenous mouse Aβ in the spinal cord. To determine whether the increase in ApoE was a potential cause or a secondary effect of neurodegeneration, the investigators crossed their mouse model of Parkinson disease to ApoE knockout mice. Interestingly, they found that deleting ApoE attenuated neurological symptoms and decreased Aβ levels in the spinal cord of their mouse model of Parkinson’s.

    These findings suggest that ApoE modifies α-synuclein-mediated neurodegeneration. Since α-synuclein is mainly intracellular and ApoE is primarily extracellular, it seems unlikely that ApoE influences α-synuclein via direct binding. The authors suggest that ApoE alters the ubiquitin/proteasome system (UPS); however, the differences the authors observed in the UPS may be secondary to downstream changes rather than direct effects of ApoE. Interestingly, α-synuclein is less soluble in mice expressing ApoE, suggesting that ApoE may affect either the aggregation of α-synuclein or the lipid associated with α-synuclein. Perhaps ApoE alters cellular lipids in a way that affects the formation of α-synuclein inclusions and subsequent neurodegeneration.

    This paper prompts many questions that will need to be answered by further experiments and analysis. How does ApoE affect α-synuclein? Does ApoE play an important role in human synucleinopathies? What is the relevance of Aβ to neurodegeneration in synucleinopathies?

    View all comments by Suzanne Wahrle