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Normal cellular prion protein protects against manganese-induced oxidative stress and apoptotic cell death

Christopher J Choi1, Vellareddy Anantharam, Nathan J Saetveit

  • 1Neuroscience and Toxicology Graduate Programs, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, Iowa 50011, USA.

Toxicological Sciences : an Official Journal of the Society of Toxicology
|May 8, 2007
PubMed

Insights

The prion protein (PrP(C)) protects neural cells from manganese (Mn) neurotoxicity by reducing Mn uptake and mitigating oxidative stress. This suggests a crucial role for PrP(C) in preventing metal-induced cellular damage.

Area of Science:

  • Neuroscience
  • Toxicology
  • Cell Biology

Background:

  • The normal prion protein (PrP(C)) is abundant in the central nervous system, but its function is not fully understood.
  • PrP(C) contains octapeptide repeat regions that bind divalent metals, hinting at a role in modulating metal toxicity.

Purpose of the Study:

  • To investigate whether PrP(C) influences the neurotoxicity of manganese (Mn).
  • To compare the effects of Mn on neural cells with and without PrP(C).

Main Methods:

  • Compared Mn-induced cytotoxicity in mouse neural cells expressing PrP(C) (PrP(C)-cells) versus prion-knockout cells (PrP(KO)-cells).
  • Analyzed intracellular Mn levels, metal transporter expression, mitochondrial function, reactive oxygen species (ROS) generation, glutathione (GSH) levels, and apoptosis markers (caspase-9, -3, DNA fragmentation).

Main Results:

  • PrP(C)-cells exhibited greater resistance to Mn-induced cytotoxicity than PrP(KO)-cells.
  • PrP(C)-cells showed reduced intracellular Mn accumulation, attenuated mitochondrial depolarization, and less ROS generation compared to PrP(KO)-cells.
  • PrP(C) protected against Mn-induced GSH depletion, caspase activation, and DNA fragmentation.

Conclusions:

  • Prion protein (PrP(C)) plays a protective role against manganese neurotoxicity.
  • PrP(C) appears to interfere with Mn uptake and reduce Mn-induced oxidative stress and apoptosis.

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