How prions kill neurons

Hippocampal neuron Prion diseases are fatal neurodegenerative disorders that cause memory loss, impaired coordination, and abnormal movements. The molecular culprit in prion diseases is PrPSc, an infectious isoform of a host-encoded glycoprotein (PrPC) that can propagate itself by a self-templating mechanism. Whether PrPSc itself is toxic to neurons, and if so, the cellular mechanisms by which it produces neuronal pathology is unknown, in part because of the absence of suitable cell culture models.

This paper describes a hippocampal neuronal cultural system to detect the toxic effect of PrPSc on dendritic spines, which are postsynaptic elements responsible for excitatory synaptic transmission, and which are implicated in learning, memory, and the earliest stages of neurodegenerative diseases. Purified, exogenously applied PrPSc causes acute retraction of dendritic spines, an effect that is entirely dependent on expression of PrPC by target neurons, and on the on the presence of a nine-amino acid, polybasic region at the N-terminus of the PrPC molecule. Both protease-resistant and protease-sensitive forms of PrPSc cause dendritic retraction.

This culture system provides new insights into the mechanisms responsible for prion neurotoxicity, and it provides a platform for characterizing different pathogenic forms of PrPSc and testing potential therapeutic agents. Because dendritic spine loss is a common theme in many neurodegenerative conditions, including Alzheimer’s, Huntington’s, and Parkinson’s diseases, and has been suggested to contribute to clinical symptoms in patients, the researchers also suggest that their system allows direct comparisons between pathogenic mechanisms involved in prion diseases and other neurodegenerative disorders.

 

A Neuronal Culture System to Detect Prion Synaptotoxicity. (2016) PLoS Pathog 12(5): e1005623. doi: 10.1371/journal.ppat.1005623
Synaptic pathology is an early feature of prion as well as other neurodegenerative diseases. Although the self-templating process by which prions propagate is well established, the mechanisms by which prions cause synaptotoxicity are poorly understood, due largely to the absence of experimentally tractable cell culture models. Here, we report that exposure of cultured hippocampal neurons to PrPSc, the infectious isoform of the prion protein, results in rapid retraction of dendritic spines. This effect is entirely dependent on expression of the cellular prion protein, PrPC, by target neurons, and on the presence of a nine-amino acid, polybasic region at the N-terminus of the PrPC molecule. Both protease-resistant and prote- ase-sensitive forms of PrPSc cause dendritic loss. This system provides new insights into the mechanisms responsible for prion neurotoxicity, and it provides a platform for character- izing different pathogenic forms of PrPSc and testing potential therapeutic agents.

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