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Huntingtin Fragments and SOD1 Mutants Form Soluble Oligomers in the Cell

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  • Yang-Nim Park
  • Xiaohong Zhao
  • Mark Norton
  • J Paul Taylor
  • Evan Eisenberg
  • Lois E Greene

Abstract

Diffusion coefficients of huntingtin (Htt) fragments and SOD1 mutants expressed in cells were measured using fluorescence correlation spectroscopy. The diffusion mobilities of both non-pathological Htt fragments (25 polyQs) and pathological Htt fragments (103 polyQs) were much slower than expected for monomers suggesting that they oligomerize. The mobility of these fragments was unaffected by duration of expression or by over-expression of Hsp70 and Hsp40. However in cells with HttQ103 inclusions, diffusion measurements showed that the residual cytosolic HttQ103 was monomeric. These results suggest that both non-pathological and pathological Htt fragments form soluble oligomers in the cytosol with the properties of the oligomers determining whether they cause pathology. SOD1 with point mutations (A4V, G37R, and G85R) also had slower diffusional mobility than the wild-type protein whose mobility was consistent with that of a dimer. However, the decrease in mobility of the different SOD1 mutantsdid not correlate with their known pathology. Therefore, while soluble oligomers always seem to be present under conditions where cell pathology occurs, the presence of the oligomers, in itself, does not determine the extent of neuropathology.

Suggested Citation

  • 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.
    • Handle: RePEc:plo:pone00:0040329
    DOI: 10.1371/journal.pone.0040329
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    1. 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.
    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.
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