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Updated: Jun 12, 2026
09:44
Generation of Alpha-Synuclein Preformed Fibrils from Monomers and Use In Vivo
Published on: June 2, 2019
A pathologic cascade leading to synaptic dysfunction in alpha-synuclein-induced neurodegeneration.
David A Scott1, Iustin Tabarean, Yong Tang
1Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA.
Summary
Pathologic alpha-synuclein causes synaptic dysfunction by depleting essential presynaptic proteins. This study reveals a novel cascade leading to neurodegeneration and potential therapeutic targets.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Neurodegenerative diseases feature alpha-synuclein deposits, synaptic dysfunction, and dementia.
- The exact sequence of events leading from alpha-synuclein accumulation to synaptotoxicity remains unclear.
Purpose of the Study:
- To elucidate the cascade of alpha-synuclein-induced pathologic events.
- To investigate the link between alpha-synuclein and synaptic protein loss.
Main Methods:
- Developed a quantitative model using cultured neurons from transgenic mice overexpressing fluorescent-human-alpha-synuclein.
- Analyzed pathological alterations in alpha-synuclein and presynaptic protein levels over time.
- Examined synaptic structure and function, including neurotransmitter release and vesicle morphology.
Main Results:
- Overexpressing neurons exhibited neurotransmitter release deficits and enlarged synaptic vesicles.
- Several critical presynaptic proteins were undetectable in "vacant synapses" and diminished in others.
- Similar synaptic protein alterations were observed in human pathologic brains.
Conclusions:
- Pathologic alpha-synuclein triggers a cascade leading to the loss of critical presynaptic proteins.
- This loss of presynaptic proteins induces functional synaptic deficits and contributes to neurodegeneration.
- Findings suggest potential therapeutic targets for alpha-synucleinopathies.
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