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Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death

Author

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  • Montserrat Arrasate

    (University of California
    University of California)

  • Siddhartha Mitra

    (University of California
    University of California
    University of California)

  • Erik S. Schweitzer

    (University of California School of Medicine)

  • Mark R. Segal

    (University of California)

  • Steven Finkbeiner

    (University of California
    University of California
    University of California
    University of California)

Abstract

Huntington's disease is caused by an abnormal polyglutamine expansion within the protein huntingtin and is characterized by microscopic inclusion bodies of aggregated huntingtin and by the death of selected types of neuron. Whether inclusion bodies are pathogenic, incidental or a beneficial coping response is controversial. To resolve this issue we have developed an automated microscope that returns to precisely the same neuron after arbitrary intervals, even after cells have been removed from the microscope stage. Here we show, by survival analysis, that neurons die in a time-independent fashion but one that is dependent on mutant huntingtin dose and polyglutamine expansion; many neurons die without forming an inclusion body. Rather, the amount of diffuse intracellular huntingtin predicts whether and when inclusion body formation or death will occur. Surprisingly, inclusion body formation predicts improved survival and leads to decreased levels of mutant huntingtin elsewhere in a neuron. Thus, inclusion body formation can function as a coping response to toxic mutant huntingtin.

Suggested Citation

  • Montserrat Arrasate & Siddhartha Mitra & Erik S. Schweitzer & Mark R. Segal & Steven Finkbeiner, 2004. "Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death," Nature, Nature, vol. 431(7010), pages 805-810, October.
    • Handle: RePEc:nat:nature:v:431:y:2004:i:7010:d:10.1038_nature02998
    DOI: 10.1038/nature02998
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    Cited by:

    1. Yang-Nim Park & Xiaohong Zhao & Mark Norton & J Paul Taylor & Evan Eisenberg & Lois E Greene, 2012. "Huntingtin Fragments and SOD1 Mutants Form Soluble Oligomers in the Cell," PLOS ONE, Public Library of Science, vol. 7(6), pages 1-12, June.
    2. Qi Wang & Joshua L Johnson & Nathalie YR Agar & Jeffrey N Agar, 2008. "Protein Aggregation and Protein Instability Govern Familial Amyotrophic Lateral Sclerosis Patient Survival," PLOS Biology, Public Library of Science, vol. 6(7), pages 1-19, July.
    3. Khalid A. Ibrahim & Kristin S. Grußmayer & Nathan Riguet & Lely Feletti & Hilal A. Lashuel & Aleksandra Radenovic, 2023. "Label-free identification of protein aggregates using deep learning," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    4. Neeraj Pandey & Mark T Fahey & Yuh-Jiin I Jong & Karen L O'Malley, 2012. "Sequences Located within the N-Terminus of the PD-Linked LRRK2 Lead to Increased Aggregation and Attenuation of 6-Hydroxydopamine-Induced Cell Death," PLOS ONE, Public Library of Science, vol. 7(9), pages 1-10, September.
    5. Arthur Fischbach & Angela Johns & Kara L. Schneider & Xinxin Hao & Peter Tessarz & Thomas Nyström, 2023. "Artificial Hsp104-mediated systems for re-localizing protein aggregates," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    6. Aaron M Streets & Yannick Sourigues & Ron R Kopito & Ronald Melki & Stephen R Quake, 2013. "Simultaneous Measurement of Amyloid Fibril Formation by Dynamic Light Scattering and Fluorescence Reveals Complex Aggregation Kinetics," PLOS ONE, Public Library of Science, vol. 8(1), pages 1-10, January.
    7. Bankanidhi Sahoo & Irene Arduini & Kenneth W Drombosky & Ravindra Kodali & Laurie H Sanders & J Timothy Greenamyre & Ronald Wetzel, 2016. "Folding Landscape of Mutant Huntingtin Exon1: Diffusible Multimers, Oligomers and Fibrils, and No Detectable Monomer," PLOS ONE, Public Library of Science, vol. 11(6), pages 1-22, June.
    8. H. F. Fisher & R. J. Boys & C. S. Gillespie & C. J. Proctor & A. Golightly, 2022. "Parameter inference for a stochastic kinetic model of expanded polyglutamine proteins," Biometrics, The International Biometric Society, vol. 78(3), pages 1195-1208, September.

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