Clues to how alpha-synuclein damages neurons in Parkinson's disease

Authors

  • David Sulzer PhD

    Corresponding author
    1. Departments of Neurology, Pharmacology, and Psychiatry, Columbia University Medical School; New York State Psychiatric Institute, New York, New York, USA
    • Departments of Neurology, Pharmacology, and Psychiatry, Columbia University Medical School, New York State Psychiatric Institute, Black 309, 650 West 168th Street, New York, New York 10032
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  • Potential conflict of interest: None reported.

Abstract

Alpha-synuclein (α-syn) appears to normally regulate neurotransmitter release, possibly via calcium-dependent binding and dissociation from lipid domains on secretory vesicles. The pathogenic effects of α-syn leading to Parkinson's disease (PD) appear to result from alternate toxic effects on lipid membrane. A variety of findings indicate that overexpression of wild-type α-syn, pathogenic mutations of α-syn, and dopamine-modified-α-syn promote toxic interaction between α-syn oligomers and lipids. These may disrupt transmembrane concentration gradients across secretory vesicles and other organelles and interfere with normal lysosomal or ubiqutin/proteasome mediated protein degradation or mitochondrial function. Additional causes of PD may interfere at other points with normal handling and degradation of α-syn, providing a variety of entry points to a converging neurodegenerative path underlying the disease. © 2010 Movement Disorder Society

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