A precipitating role for truncated α-synuclein and the proteasome in α-synuclein aggregation

Implications for pathogenesis of parkinson disease

Chang Wei Liu, Benoit I. Giasson, Karen A. Lewis, Virginia M. Lee, George N. DeMartino, Philip J. Thomas

Research output: Contribution to journalArticle

171 Citations (Scopus)

Abstract

Parkinson disease and other α-synucleinopathies are characterized by the deposition of intraneuronal α-synuclein (αSyn) inclusions. A significant fraction (about 15%) of αSyn in these pathological structures are truncated forms that have a much higher propensity than the full-length αSyn to form aggregates in vitro. However, little is known about the role of truncated αSyn species in pathogenesis or the means by which they are generated. Here, we have provided an in vitro mechanistic study demonstrating that truncated αSyns induce rapid aggregation of full-length protein at substoichiometric ratios. Co-overexpression of truncated αSyn with full-length protein increases cell vulnerability to oxidative stress in dopaminergic SH-SY5Y cells. These results suggest a precipitating role for truncated αSyn in the pathogenesis of diseases involving αSyn aggregation. In this regard, the A53T mutation found in some cases of familial Parkinson disease exacerbates the accumulation of insoluble αSyns that correlates with the onset of pathology in transgenic mice expressing human αSyn-A53T mutant. The caspase-like activity of the 20 S proteasome produces truncated fragments similar to those found in patients and animal models from degradation of unstructured αSyn. We propose a model in which incomplete degradation of αSyn, especially under overloaded proteasome capacity, produces highly amyloidogenic fragments that rapidly induce the aggregation of full-length protein. These aggregates in turn reduce proteasome activity, leading to further accumulation of fragmented and full-length αSyns, creating a vicious cycle of cytotoxicity. This model has parallels in other neurodegenerative diseases, such as Huntington disease, where coaggregation of poly(Q) fragments with full-length protein has been observed.

Original languageEnglish (US)
Pages (from-to)22670-22678
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number24
DOIs
StatePublished - Jun 17 2005

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Synucleins
Proteasome Endopeptidase Complex
Parkinson Disease
Agglomeration
Proteins
Neurodegenerative diseases
Degradation
Oxidative stress
Huntington Disease
Pathology
Cytotoxicity
Caspases
Neurodegenerative Diseases
Transgenic Mice
Animals
Oxidative Stress
Animal Models

ASJC Scopus subject areas

  • Biochemistry

Cite this

A precipitating role for truncated α-synuclein and the proteasome in α-synuclein aggregation : Implications for pathogenesis of parkinson disease. / Liu, Chang Wei; Giasson, Benoit I.; Lewis, Karen A.; Lee, Virginia M.; DeMartino, George N.; Thomas, Philip J.

In: Journal of Biological Chemistry, Vol. 280, No. 24, 17.06.2005, p. 22670-22678.

Research output: Contribution to journalArticle

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