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Alternative α-synuclein transcript usage as a convergent mechanism in Parkinson's disease pathology

Author

Listed:
  • Herve Rhinn

    (Center for Neurobiology and Behavior, and Taub Institute, Columbia University, College of Physicians and Surgeons 15-403)

  • Liang Qiang

    (Center for Neurobiology and Behavior, and Taub Institute, Columbia University, College of Physicians and Surgeons 15-403)

  • Toru Yamashita

    (Center for Neurobiology and Behavior, and Taub Institute, Columbia University, College of Physicians and Surgeons 15-403)

  • David Rhee

    (Center for Neurobiology and Behavior, and Taub Institute, Columbia University, College of Physicians and Surgeons 15-403)

  • Ari Zolin

    (Center for Neurobiology and Behavior, and Taub Institute, Columbia University, College of Physicians and Surgeons 15-403)

  • William Vanti

    (Center for Neurobiology and Behavior, and Taub Institute, Columbia University, College of Physicians and Surgeons 15-403)

  • Asa Abeliovich

    (Center for Neurobiology and Behavior, and Taub Institute, Columbia University, College of Physicians and Surgeons 15-403)

Abstract

α-Synuclein is implicated both in physiological functions at neuronal synaptic terminals as well as in pathological processes in the context of Parkinson's disease. However, the molecular mechanisms for these apparently diverse roles are unclear. Here we show that specific RNA transcript isoforms of α-synuclein with an extended 3′ untranslated region, termed aSynL, appear selectively linked to pathological processes, relative to shorter α-synuclein transcripts. Common variants in the aSynL 3′ untranslated region associated with Parkinson's disease risk promote the accumulation and translation of aSynL transcripts. The presence of intracellular dopamine can further enhance the relative abundance of aSynL transcripts through alternative polyadenylation site selection. We demonstrate that the presence of the extended aSynL transcript 3′ untranslated region impacts accumulation of α-synuclein protein, which appears redirected away from synaptic terminals and towards mitochondria, reminiscent of Parkinson's disease pathology. Taken together, these findings identify a novel mechanism for aSyn regulation in the context of Parkinson's disease-associated genetic and environmental variations.

Suggested Citation

  • Herve Rhinn & Liang Qiang & Toru Yamashita & David Rhee & Ari Zolin & William Vanti & Asa Abeliovich, 2012. "Alternative α-synuclein transcript usage as a convergent mechanism in Parkinson's disease pathology," Nature Communications, Nature, vol. 3(1), pages 1-11, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms2032
    DOI: 10.1038/ncomms2032
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    Cited by:

    1. Ya Cui & Frederick J. Arnold & Fanglue Peng & Dan Wang & Jason Sheng Li & Sebastian Michels & Eric J. Wagner & Albert R. Spada & Wei Li, 2023. "Alternative polyadenylation transcriptome-wide association study identifies APA-linked susceptibility genes in brain disorders," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Zhiping Zhang & Bongmin Bae & Winston H. Cuddleston & Pedro Miura, 2023. "Coordination of alternative splicing and alternative polyadenylation revealed by targeted long read sequencing," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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