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Cited by 824Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingAlzheimer's disease research and treatments

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

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Lee, Michael K., Stirling, Wanda, Xu, Yanqun, Xu, Xueying, Qui, Dike, Mandir, Allen S., Dawson, Ted M., Copeland, Neal G. +2 more·2002·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.132197599PMC PMC124407
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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.

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  • Mitochondrial degeneration has been implicated in a-synucleinopathy and a-syn transgenic flies show abnormal mitochondrial morphology.

    “Mitochondrial degeneration has been implicated in a-synucleinopathy (13,25) and a-syn transgenic flies show abnormal mitochondrial morphology (16).”

    From Enhanced mTORC1 signaling and Protein Synthesis in Parkinson’s Disease Pathogenesis Disease Pathogenesis (2022) · cites this paper as [13]

    The citation to this paper is attached to the claim that mitochondrial degeneration has been implicated in α-synucleinopathy; the statement about transgenic flies has a separate citation. The Results describe α-synuclein, ubiquitin, and neurofilament abnormalities in transgenic mice, but searches for mitochondrial degeneration and mitochondrial morphology found no passage addressing the cited claim. Page numbers were not available in our copy. (LLM, conf=0.73)

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Cited by

Sorted by citations

Authors
Lee, M. K., Stirling, W., Xu, Y., Xu, X., Qui, D., Mandir, A. S., Dawson, T. M., Copeland, N. G., Jenkins, N. A., & Price, D. L.
Affiliations
Johns Hopkins University (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2002-06-25
Volume
99
Issue
13
Pages
8968-8973
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.132197599
PMC
PMC124407
OpenAlex
W1986628169
Cited by
824
References
2
Citations by year
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FWCI
33.85
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (NS38377)
  • National Institute on Aging (AG 14248, P01AG014248)
  • National Institute of Neurological Disorders and Stroke (NS 38377, P01NS038065, R56NS038065, P50NS038377, NS 38065, R01NS038065)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
alpha-synuclein, familial Parkinson's disease, A53T mutation, A30P mutation, transgenic mice, neurodegeneration, protein aggregation, Lewy bodies, Lewy neurites, ubiquitin, motor impairment, neurotoxicity
MeSH terms
Alanine, Animals, Humans, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Parkinson Disease, Threonine, Reverse Transcriptase Polymerase Chain Reaction, Mice, Synucleins, alpha-Synuclein

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