Clearance of α-Synuclein Oligomeric Intermediates via the Lysosomal Degradation Pathway

He Jin Lee, Farnaz Khoshaghideh, Smita Patel, Seung-Jae Lee

Research output: Contribution to journalArticle

272 Citations (Scopus)

Abstract

Cytoplasmic deposition of α-synuclein aggregates is a common pathological feature of many neurodegenerative diseases. Strong evidence for the causative role of α-synuclein in these disorders is provided by genetic linkage between this gene and familial Parkinson's disease and by neurodegeneration in transgenic animals that overexpress this protein. In particular, it has been hypothesized that the accumulation of nonfibrillar oligomers of α-synuclein, which serve as intermediates for fibrillar inclusion body formation, causes neurodegeneration. However, little is known about how cells handle potentially toxic protein aggregates. Here we demonstrate that cells are capable of clearing preformed α-synuclein aggregates via the lysosomal degradation pathway. Consequently, blocking this pathway causes the accumulation of the aggregates in non-neuronal cells, differentiated neuroblastoma cells, and primary cortical neurons. This aggregate clearance occurs in an aggregation stage-specific manner; oligomeric intermediates are susceptible to clearance, whereas mature fibrillar inclusion bodies are not. Neutralization of the acidic compartments leads to the accumulation of α-synuclein aggregates and exacerbates α-synuclein toxicity in postmitotic neuronal cells, suggesting that the accumulation of oligomeric intermediates may be an important event leading to α-synuclein-mediated cell death. These results suggest that enhancing lysosomal function may be a potential therapeutic strategy to halt or even prevent the pathogenesis of Parkinson's disease and other Lewy body diseases.

Original languageEnglish
Pages (from-to)1888-1896
Number of pages9
JournalJournal of Neuroscience
Volume24
Issue number8
DOIs
StatePublished - 25 Feb 2004

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Synucleins
Inclusion Bodies
Parkinson Disease
Lewy Body Disease
Genetically Modified Animals
Genetic Linkage
Poisons
Neuroblastoma
Neurodegenerative Diseases
Cell Death
Neurons

Keywords

  • Lewy body
  • Lysosome
  • Neurodegeneration
  • Parkinson's disease
  • Protein aggregation
  • α-synuclein

Cite this

Lee, He Jin ; Khoshaghideh, Farnaz ; Patel, Smita ; Lee, Seung-Jae. / Clearance of α-Synuclein Oligomeric Intermediates via the Lysosomal Degradation Pathway. In: Journal of Neuroscience. 2004 ; Vol. 24, No. 8. pp. 1888-1896.
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Clearance of α-Synuclein Oligomeric Intermediates via the Lysosomal Degradation Pathway. / Lee, He Jin; Khoshaghideh, Farnaz; Patel, Smita; Lee, Seung-Jae.

In: Journal of Neuroscience, Vol. 24, No. 8, 25.02.2004, p. 1888-1896.

Research output: Contribution to journalArticle

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