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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 RIS Download

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

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Associated grants

  • Agency: NINDS NIH HHS, Id: NS38065
  • Agency: NIA NIH HHS, Id: AG14248
  • Agency: NINDS NIH HHS, Id: NS38377
  • Agency: NIA NIH HHS, Id: P01 AG014248
  • Agency: NINDS NIH HHS, Id: R01 NS038065
  • Agency: NINDS NIH HHS, Id: P01 NS038065
  • Agency: NINDS NIH HHS, Id: R56 NS038065
  • Agency: NINDS NIH HHS, Id: P50 NS038377

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