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

Mutations in alpha-synuclein (alpha-Syn) cause Parkinson's disease (PD) in a small number of pedigrees with familial PD. Moreover, alpha-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 alpha-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 alpha-Syns. The mice expressing the A53T human alpha-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 alpha-Syn and ubiquitin. Consistent with abnormal neuronal accumulation of alpha-Syn, brain regions with pathology exhibit increases in detergent-insoluble alpha-Syn and alpha-Syn aggregates. Our results demonstrate that the A53T mutant alpha-Syn causes significantly greater in vivo neurotoxicity as compared with other alpha-Syn variants. Further, alpha-Syn-dependent neurodegeneration is associated with abnormal accumulation of detergent-insoluble alpha-Syn.

Pubmed ID: 12084935

Authors

  • Lee MK
  • Stirling W
  • Xu Y
  • Xu X
  • Qui D
  • Mandir AS
  • Dawson TM
  • Copeland NG
  • Jenkins NA
  • Price DL

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

June 25, 2002

Associated Grants

  • Agency: NIA NIH HHS, Id: AG14248
  • Agency: NINDS NIH HHS, Id: NS38065
  • Agency: NINDS NIH HHS, Id: NS38377

Mesh Terms

  • Alanine
  • Animals
  • Humans
  • Mice
  • Mice, Transgenic
  • Mutation
  • Nerve Tissue Proteins
  • Parkinson Disease
  • Reverse Transcriptase Polymerase Chain Reaction
  • Synucleins
  • Threonine
  • alpha-Synuclein