Ubiquitination of α-Synuclein in Lewy Bodies Is a Pathological Event Not Associated with Impairment of Proteasome Function

George K. Tofaris, Azam Razzaq, Bernardino Ghetti, Kathryn S. Lilley, Maria Grazia Spillantini

Research output: Contribution to journalArticle

238 Citations (Scopus)

Abstract

Lewy bodies are intracellular fibrillar inclusions composed of α-synuclein. They constitute the pathological hallmark of Parkinson's disease, dementia with Lewy bodies, and other neurodegenerative diseases. Although the majority of Lewy bodies are stained for ubiquitin by immunohistochemistry, the substrate for this modification is poorly understood. Insoluble, urea-soluble α-synuclein was separated from soluble fractions and subjected to two-dimensional gel electrophoresis to further characterize pathogenic α-synuclein species from disease brains. By using this approach, we found that in sporadic Lewy body diseases a highly modified, disease-associated 22-24-kDa α-synuclein species is ubiquitinated. Conjugation of one, two, and, to a lesser extent, three ubiquitins was detected. This 22-24-kDa α-synuclein species represents partly phosphorylated protein. Furthermore, no generalized impairment of the proteolytic activity of the proteasome was detected in brain regions with Lewy body pathology. Because unmodified α-synuclein is degraded by the proteasome in a ubiquitin-independent manner, these data suggest that accumulation of modified 22-24-kDa α-synuclein is a disease-specific event which may overwhelm the proteolytic system, leading to aberrant ubiquitination. Accordingly, carboxyl-terminal-truncated α-synuclein, presumably the result of aberrant proteolysis, is found only in association with α-synuclein aggregates.

Original languageEnglish
Pages (from-to)44405-44411
Number of pages7
JournalJournal of Biological Chemistry
Volume278
Issue number45
DOIs
StatePublished - Nov 7 2003

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Synucleins
Lewy Bodies
Ubiquitination
Proteasome Endopeptidase Complex
Lewy Body Disease
Ubiquitin
Brain
Ubiquitins
Neurodegenerative diseases
Proteolysis
Electrophoresis, Gel, Two-Dimensional
Brain Diseases
Pathology
Electrophoresis
Neurodegenerative Diseases
Parkinson Disease
Urea
Gels
Immunohistochemistry
Association reactions

ASJC Scopus subject areas

  • Biochemistry

Cite this

Ubiquitination of α-Synuclein in Lewy Bodies Is a Pathological Event Not Associated with Impairment of Proteasome Function. / Tofaris, George K.; Razzaq, Azam; Ghetti, Bernardino; Lilley, Kathryn S.; Spillantini, Maria Grazia.

In: Journal of Biological Chemistry, Vol. 278, No. 45, 07.11.2003, p. 44405-44411.

Research output: Contribution to journalArticle

Tofaris, George K. ; Razzaq, Azam ; Ghetti, Bernardino ; Lilley, Kathryn S. ; Spillantini, Maria Grazia. / Ubiquitination of α-Synuclein in Lewy Bodies Is a Pathological Event Not Associated with Impairment of Proteasome Function. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 45. pp. 44405-44411.
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