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Disruption of mitochondrial complex I induces progressive parkinsonism

Author

Listed:
  • Patricia González-Rodríguez

    (Northwestern University)

  • Enrico Zampese

    (Northwestern University)

  • Kristen A. Stout

    (Northwestern University)

  • Jaime N. Guzman

    (Northwestern University)

  • Ema Ilijic

    (Northwestern University)

  • Ben Yang

    (Northwestern University)

  • Tatiana Tkatch

    (Northwestern University)

  • Mihaela A. Stavarache

    (Weill Cornell Medical College)

  • David L. Wokosin

    (Northwestern University)

  • Lin Gao

    (Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla and CIBERNED)

  • Michael G. Kaplitt

    (Weill Cornell Medical College)

  • José López-Barneo

    (Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla and CIBERNED)

  • Paul T. Schumacker

    (Northwestern University)

  • D. James Surmeier

    (Northwestern University)

Abstract

Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson’s disease1. Yet, whether this change contributes to Parkinson’s disease pathogenesis is unclear2. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism—which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson’s disease paradigm3,4.

Suggested Citation

  • Patricia González-Rodríguez & Enrico Zampese & Kristen A. Stout & Jaime N. Guzman & Ema Ilijic & Ben Yang & Tatiana Tkatch & Mihaela A. Stavarache & David L. Wokosin & Lin Gao & Michael G. Kaplitt & J, 2021. "Disruption of mitochondrial complex I induces progressive parkinsonism," Nature, Nature, vol. 599(7886), pages 650-656, November.
  • Handle: RePEc:nat:nature:v:599:y:2021:i:7886:d:10.1038_s41586-021-04059-0
    DOI: 10.1038/s41586-021-04059-0
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    Citations

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    Cited by:

    1. Thomas M. Goralski & Lindsay Meyerdirk & Libby Breton & Laura Brasseur & Kevin Kurgat & Daniella DeWeerd & Lisa Turner & Katelyn Becker & Marie Adams & Daniel J. Newhouse & Michael X. Henderson, 2024. "Spatial transcriptomics reveals molecular dysfunction associated with cortical Lewy pathology," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Kimberly C. Paul & Richard C. Krolewski & Edinson Lucumi Moreno & Jack Blank & Kristina M. Holton & Tim Ahfeldt & Melissa Furlong & Yu Yu & Myles Cockburn & Laura K. Thompson & Alexander Kreymerman & , 2023. "A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Blanca Jiménez-Gómez & Patricia Ortega-Sáenz & Lin Gao & Patricia González-Rodríguez & Paula García-Flores & Navdeep Chandel & José López-Barneo, 2023. "Transgenic NADH dehydrogenase restores oxygen regulation of breathing in mitochondrial complex I-deficient mice," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Shuangshuang Sun & Zhe Xu & Liying He & Yihui Shen & Yuqing Yan & Xubing Lv & Xujing Zhu & Wei Li & Wei-Ya Tian & Yongjun Zheng & Sen Lin & Yadong Sun & Lei Li, 2024. "Metabolic regulation of cytoskeleton functions by HDAC6-catalyzed α-tubulin lactylation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Pascale Baden & Maria Jose Perez & Hariam Raji & Federico Bertoli & Stefanie Kalb & María Illescas & Fokion Spanos & Claudio Giuliano & Alessandra Maria Calogero & Marvin Oldrati & Hannah Hebestreit &, 2023. "Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    6. Woori Kim & Mohit Tripathi & Chunhyung Kim & Satyapavan Vardhineni & Young Cha & Shamseer Kulangara Kandi & Melissa Feitosa & Rohit Kholiya & Eric Sah & Anuj Thakur & Yehan Kim & Sanghyeok Ko & Kaiya , 2023. "An optimized Nurr1 agonist provides disease-modifying effects in Parkinson’s disease models," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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