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

PLoS Pathog. 2015 Aug 4;11(8):e1005073. doi: 10.1371/journal.ppat.1005073. eCollection 2015 Aug.

Abstract

In prion diseases, synapse dysfunction, axon retraction and loss of neuronal polarity precede neuronal death. The mechanisms driving such polarization defects, however, remain unclear. Here, we examined the contribution of RhoA-associated coiled-coil containing kinases (ROCK), key players in neuritogenesis, to prion diseases. We found that overactivation of ROCK signaling occurred in neuronal stem cells infected by pathogenic prions (PrPSc) and impaired the sprouting of neurites. In reconstructed networks of mature neurons, PrPSc-induced ROCK overactivation provoked synapse disconnection and dendrite/axon degeneration. This overactivation of ROCK also disturbed overall neurotransmitter-associated functions. Importantly, we demonstrated that beyond its impact on neuronal polarity ROCK overactivity favored the production of PrPSc through a ROCK-dependent control of 3-phosphoinositide-dependent kinase 1 (PDK1) activity. In non-infectious conditions, ROCK and PDK1 associated within a complex and ROCK phosphorylated PDK1, conferring basal activity to PDK1. In prion-infected neurons, exacerbated ROCK activity increased the pool of PDK1 molecules physically interacting with and phosphorylated by ROCK. ROCK-induced PDK1 overstimulation then canceled the neuroprotective α-cleavage of normal cellular prion protein PrPC by TACE α-secretase, which physiologically precludes PrPSc production. In prion-infected cells, inhibition of ROCK rescued neurite sprouting, preserved neuronal architecture, restored neuronal functions and reduced the amount of PrPSc. In mice challenged with prions, inhibition of ROCK also lowered brain PrPSc accumulation, reduced motor impairment and extended survival. We conclude that ROCK overactivation exerts a double detrimental effect in prion diseases by altering neuronal polarity and triggering PrPSc accumulation. Eventually ROCK emerges as therapeutic target to combat prion diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Disease Models, Animal
  • Fluorescent Antibody Technique
  • Immunoprecipitation
  • Lab-On-A-Chip Devices
  • Mice
  • Mice, Inbred C57BL
  • Neurites / metabolism
  • Neurogenesis
  • PrPC Proteins / metabolism
  • PrPSc Proteins / metabolism*
  • Prion Diseases / metabolism*
  • Prion Diseases / pathology*
  • rho-Associated Kinases / metabolism*

Substances

  • PrPC Proteins
  • PrPSc Proteins
  • rho-Associated Kinases

Grant support

This work was supported by the French Agence Nationale de la Recherche (Prions&SensiTNF, n°131201) and INSERM. SN is a post-doctoral fellow of French Agence Nationale de la Recherche. AAB is funded by Domaine d’Intérêt Majeur – Maladies Infectieuses – Région Ile de France. PT is a postdoctoral fellow funded by ERANET NEURON "MICRODEG" project. This work was also supported by the European Joint Program on Neurodegenerative Diseases and Agence Nationale de la Recherche – "PrPC&PDK1" – n° ANR-14-JPCD-0003-01. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.