Related Experiment Video
Updated: Aug 20, 2026
Investigating the Spreading and Toxicity of Prion-like Proteins Using the Metazoan Model Organism C. elegans
Published on: January 8, 2015
Mitochondrial localization of cellular prion protein (PrPC) invokes neuronal apoptosis in aged transgenic mice
Naomi S Hachiya1, Makiko Yamada, Kota Watanabe
1Department of a Cortical Function Disorders, National Institute of Neuroscience (NIN), National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo 187-8502, Japan.
Abstract:
Recent studies suggest that the disease isoform of prion protein (PrPSc) is non-neurotoxic in the absence of cellular isoform of prion protein (PrPC), indicating that PrPC may participate directly in the neurodegenerative damage by itself. Meanwhile, transgenic mice harboring a high-copy-number of wild-type mouse (Mo) PrPC develop a spontaneous neurological dysfunction in an age-dependent manner, even without inoculation of PrPSc and thus, investigations of these aged transgenic mice may lead to the understanding how PrPC participate in the neurotoxic property of PrP. Here we demonstrate mitochondria-mediated neuronal apoptosis in aged transgenic mice overexpressing wild-type MoPrPC (Tg(MoPrP)4053/FVB). The aged mice exhibited an aberrant mitochondrial localization of PrPC concomitant with decreased proteasomal activity, while younger littermates did not. Such aberrant mitochondrial localization was accompanied by decreased mitochondrial manganese superoxide dismutase (Mn-SOD) activity, cytochrome c release into the cytosol, caspase-3 activation, and DNA fragmentation, most predominantly in hippocampal neuronal cells. Following cell culture studies confirmed that decrease in the proteasomal activity is fundamental for the PrPC-related, mitochondria-mediated apoptosis. Hence, the neurotoxic property of PrPC could be explained by the mitochondria-mediated neuronal apoptosis, at least in part.
Insights
Cellular prion protein (PrPC) overload in mice triggers age-dependent neurodegeneration. This study reveals PrPC accumulation in mitochondria, leading to neuronal apoptosis and dysfunction, independent of disease-associated prion protein (PrPSc).
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Cellular prion protein (PrPC) is implicated in neurodegenerative diseases, but its intrinsic neurotoxic mechanisms are unclear.
- Transgenic mice overexpressing wild-type PrPC develop spontaneous neurological dysfunction, offering a model to study PrPC's role in neurodegeneration.
- The absence of disease-associated prion protein (PrPSc) suggests PrPC itself may drive neurotoxicity.
Purpose of the Study:
- To investigate the mechanisms underlying mitochondria-mediated neuronal apoptosis in aged transgenic mice overexpressing wild-type mouse (Mo) PrPC.
- To determine the role of aberrant PrPC mitochondrial localization and proteasomal activity in PrPC-induced neurotoxicity.
Main Methods:
- Utilized aged transgenic mice (Tg(MoPrP)4053/FVB) overexpressing wild-type MoPrPC and younger littermates as controls.
- Assessed mitochondrial PrPC localization, proteasomal activity, mitochondrial manganese superoxide dismutase (Mn-SOD) activity, cytochrome c release, caspase-3 activation, and DNA fragmentation.
- Conducted cell culture studies to confirm the role of proteasomal activity in PrPC-related apoptosis.
Main Results:
- Aged transgenic mice exhibited aberrant mitochondrial localization of PrPC and decreased proteasomal activity compared to younger controls.
- Aberrant mitochondrial PrPC was associated with reduced Mn-SOD activity, cytochrome c release, caspase-3 activation, and DNA fragmentation, particularly in hippocampal neurons.
- Cell culture experiments confirmed that reduced proteasomal activity is crucial for PrPC-mediated, mitochondria-dependent apoptosis.
Conclusions:
- Overexpression of wild-type PrPC can induce neurotoxicity through mitochondria-mediated neuronal apoptosis.
- Aberrant mitochondrial localization of PrPC and impaired proteasomal function are key events in this neurodegenerative process.
- These findings suggest that PrPC itself possesses intrinsic neurotoxic properties mediated by mitochondrial dysfunction.
