Human α-synuclein-harboring familial Parkinson's disease-linked Ala-53 → Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice

Michael K. Lee, Wanda Stirling, Yanqun Xu, Eying Xu, Dike Qui, Allen S. Mandir, Ted M Dawson, Neal G. Copeland, Nancy A. Jenkins, Don L. Price

Research output: Contribution to journalArticle

Abstract

Mutations in α-synuclein (α-Syn) cause Parkinson's disease (PD) in a small number of pedigrees with familial PD. Moreover, α-Syn accumulates as a major component of Lewy bodies and Lewy neurites, intraneuronal inclusions that are neuropathological hallmarks of PD. To better understand the pathogenic relationship between alterations in the biology of α-Syn and PD-associated neurodegeneration, we generated multiple lines of transgenic mice expressing high levels of either wild-type or familial PD-linked Ala-30 → Pro (A30P) or Ala-53 → Thr (A53T) human α-Syns. The mice expressing the A53T human α-Syn, but not wild-type or the A30P variants, develop adult-onset neurodegenerative disease with a progressive motoric dysfunction leading to death. Pathologically, affected mice exhibit neuronal abnormalities (in perikarya and neurites) including pathological accumulations of α-Syn and ubiquitin. Consistent with abnormal neuronal accumulation of α-Syn, brain regions with pathology exhibit increases in detergent-insoluble α-Syn and α-Syn aggregates. Our results demonstrate that the A53T mutant α-Syn causes significantly greater in vivo neurotoxicity as compared with other α-Syn variants. Further, α-Syn-dependent neurodegeneration is associated with abnormal accumulation of detergent-insoluble α-Syn.

Original languageEnglish (US)
Pages (from-to)8968-8973
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number13
DOIs
StatePublished - Jun 25 2002

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Synucleins
Neurodegenerative Diseases
Transgenic Mice
Parkinson Disease
Mutation
Neurites
Detergents
Lewy Bodies
Pedigree
Ubiquitin
Pathology
Brain

ASJC Scopus subject areas

  • Genetics
  • General

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Human α-synuclein-harboring familial Parkinson's disease-linked Ala-53 → Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice. / Lee, Michael K.; Stirling, Wanda; Xu, Yanqun; Xu, Eying; Qui, Dike; Mandir, Allen S.; Dawson, Ted M; Copeland, Neal G.; Jenkins, Nancy A.; Price, Don L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 13, 25.06.2002, p. 8968-8973.

Research output: Contribution to journalArticle

Lee, Michael K. ; Stirling, Wanda ; Xu, Yanqun ; Xu, Eying ; Qui, Dike ; Mandir, Allen S. ; Dawson, Ted M ; Copeland, Neal G. ; Jenkins, Nancy A. ; Price, Don L. / Human α-synuclein-harboring familial Parkinson's disease-linked Ala-53 → Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2002 ; Vol. 99, No. 13. pp. 8968-8973.
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