Cell Biology of α-Synuclein: Implications in Parkinson’s Disease and Other Lewy Body Diseases

  • Seung-Jae Lee
  • Yoon Suk Kim
Part of the Protein Reviews book series (PRON, volume 6)


Missense mutations and gene multiplication in the α-synuclein gene cause inherited forms of Parkinson’s disease (PD), and deposition of amyloid fibrils composed of wild-type α-synuclein in Lewy bodies and Lewy neurites is a pathologic hallmark of sporadic PD and other related neurodegenerative diseases such as dementia with Lewy bodies. These findings, along with the studies in animal models, strongly suggest that misfolding and aggregation of α-synuclein is a critical component in the pathogenesis of these disorders. Though the physiologic function of α-synuclein has not been completely defined, there has been a body of evidence supporting its roles in synaptic transmission, synaptic vesicle biogenesis, and lipid transport and metabolism. More importantly, based on the lack of neurodegenerative phenotypes in synuclein knockout animals, it has been suggested that loss of normal function of this protein might not be the direct cause of PD. α-Synuclein forms various types of nonfibrillar and fibrillar aggregates. PD-linked mutations accelerate the aggregation process in one or more steps in the fibrillation. Although some oligomeric aggregates seem to be toxic to cell, leading to functional abnormalities such as proteasomal and lysosomal dysfunctions, mitochondrial deficits, and Golgi fragmentation and transport defects, cells have defense mechanisms against these potentially toxic oligomeric aggregates. The free oligomers are transported to and deposited in the pericentriolar region by the microtubule system, resulting in the sequestration of toxic aggregates. After deposition, the transition from oligomers to fibrils occurs, forming Lewy body-like inclusion bodies and perhaps transforming toxic species into inert aggregates. Moreover, we have also shown that cells can degrade the preformed oligomers by autophagy. Elucidation of the mechanisms of the cellular aggregation process and the handling of preformed toxic aggregates should greatly enhance our understanding of the disease and provide rational targets for therapeutic intervention.


Inclusion Body Lewy Body Amyloid Fibril Inclusion Body Formation Autophagic Degradation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Seung-Jae Lee
    • 1
  • Yoon Suk Kim
    • 1
  1. 1.The Parkinson’s InstituteSunnyvaleUSA

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