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Assays for the Degradation of Misfolded Proteins in Cells
10:56

Assays for the Degradation of Misfolded Proteins in Cells

Published on: August 28, 2016

Cell death: protein misfolding and neurodegenerative diseases

Tomohiro Nakamura1, Stuart A Lipton

  • 1Center for Neuroscience, Aging and Stem Cell Research, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.

Apoptosis : an International Journal on Programmed Cell Death
|January 9, 2009
PubMed

Insights

Nitric oxide (NO) can cause protein misfolding in neurodegenerative diseases by S-nitrosylation. Memantine/NitroMemantine may prevent this by inhibiting NMDA receptor activity, reducing NO production and neurotoxicity.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • Neurodegenerative diseases involve protein misfolding and aggregation.
  • Sporadic forms may stem from environmental factors, including excessive nitric oxide (NO) and reactive oxygen species (ROS).
  • Overactive NMDA-receptors contribute to NO/ROS generation, potentially causing protein misfolding.

Purpose of the Study:

  • To investigate the role of NO in protein misfolding in neurodegenerative disorders.
  • To explore the mechanism of NO-induced protein misfolding via S-nitrosylation.
  • To evaluate the potential of memantine/NitroMemantine in mitigating NO-mediated neurotoxicity.

Main Methods:

  • Investigated NO-mediated protein misfolding.
  • Examined S-nitrosylation of protein-disulfide isomerase and parkin.
  • Assessed the effects of memantine/NitroMemantine on NMDA receptor activity, NO production, and protein misfolding.

Main Results:

  • Evidence suggests NO contributes to protein misfolding through S-nitrosylation.
  • Specific targets identified include protein-disulfide isomerase and the E3 ubiquitin ligase parkin.
  • Memantine/NitroMemantine demonstrated potential to inhibit NMDA receptor overactivity, reduce NO, and ameliorate protein misfolding.

Conclusions:

  • NO-induced S-nitrosylation is a significant mechanism in sporadic neurodegenerative protein misfolding.
  • Targeting NMDA receptor overactivity with memantine/NitroMemantine offers a therapeutic strategy.
  • This approach may reduce neurotoxicity by decreasing NO production and preventing protein aggregation.

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