Double-Edge Sword of Sustained ROCK Activation in Prion Diseases through Neuritogenesis Defects and Prion Accumulation

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Transmissible Spongiform Encephalopathies (TSEs), commonly named prion diseases, are caused by deposition in the brain of pathogenic prions PrPSc that trigger massive neuronal death. Because of our poor understanding of the mechanisms sustaining prion-induced neurodegeneration, there is to date no effective medicine to combat TSEs. The current study demonstrates that ROCK kinases are overactivated in prion-infected cells and contribute to prion pathogenesis at two levels. First, PrPSc-induced ROCK overactivation affects neuronal polarity with synapse disconnection, axon/dendrite degradation, and disturbs neuronal functions. Second, ROCK overactivity amplifies the production of pathogenic prions. The pharmacological inhibition of ROCK protects diseased neurons from PrPSc toxicity by preserving neuronal architecture and functions and lowering PrPSc level. Inhibition of ROCK in prion-infected mice reduces brain PrPSc levels, improves motor activity and extends lifespan. This study opens up new avenues to design ROCK-based therapeutic strategies to fight TSEs.

Vyšlo v časopise: Double-Edge Sword of Sustained ROCK Activation in Prion Diseases through Neuritogenesis Defects and Prion Accumulation. PLoS Pathog 11(8): e32767. doi:10.1371/journal.ppat.1005073
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005073

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